Marginal Regression Models Research Articles

Relative Effectiveness and Waning of a Third Dose of mRNA COVID-19 Vaccine in Medicare Beneficiaries Aged 65 Years and Older during the BA.1/BA.2 Omicron Period.

We assessed the added benefit and waning effectiveness of a third COVID-19 vaccine dose (original formula) for preventing COVID-19-related outcomes. We used Medicare claims data to conduct a retrospective cohort study in U.S. community-dwelling Medicare Fee-for-Service beneficiaries aged ≥65 years during the BA.1/BA.2 Omicron period (December 19, 2021 - March 26, 2022). We estimated relative vaccine effectiveness (RVE) of 3 versus 2 doses of mRNA COVID-19 vaccines using marginal structural Cox regression models. Among 8,135,020 eligible beneficiaries, 73.3% were 3-dose vaccinated by March 26, 2022. At 14-60 days since vaccination, a third dose provided significant added benefit against COVID-19-related hospitalization for Moderna (RVE: 77.2%; 95% confidence interval (CI): 76.0%, 78.4%) and Pfizer-BioNTech (RVE: 72.5%; 95% CI: 70.8%, 74.0%). Added benefit was lower >120 days. For those with prior medically attended COVID-19 diagnoses, Pfizer-BioNTech provided an added benefit for 120 days, while Moderna provided some added benefit >120 days. Added benefit for either vaccine was higher against death compared to less severe outcomes, which still decreased >120 days. A third dose COVID-19 vaccine provided significant added benefit against COVID-19-related hospitalization and death, even for beneficiaries with prior medically attended COVID-19 diagnoses. This added benefit decreased after 4 months.

A Copula Discretization of Time Series-Type Model for Examining Climate Data

The study presents a comparative analysis of climate data under two scenarios: a Gaussian copula marginal regression model for count time series data and a copula-based bivariate count time series model. These models, built after comprehensive simulations, offer adaptable autocorrelation structures considering the daily average temperature and humidity data observed at a regional airport in Mobile, AL.

Assessment of Baseline Ultrawidefield Fluorescein Angiographic Quantitative Leakage Parameters with Ultrawidefield Fundus Features and Clinical Parameters in Diabetic Retinopathy in Protocol AA

PurposeEvaluate quantitative leakage parameters on ultra-widefield fluorescein angiography (UWF-FA) images and explore their association with Diabetic Retinopathy Severity Scale (DRSS), predominantly peripheral lesions (PPLs), visual acuity, and clinical characteristics. DesignA post-hoc analysis of baseline UWF-FA images in the DRCR Retina Network observational study Protocol AA. ParticipantsN = 575 eyes from 384 adults across 38 sites in the US and Canada with gradable UWF-FA. MethodsA machine learning-enhanced feature extraction platform provided initial leakage segmentation of UWF-FA images sequentially reviewed and corrected by two certified readers for segmentation accuracy. UWF-FA leakage was measured in five retinal zones: panretinal (whole retina), central macular (3-disc diameter fovea-centered circle), posterior pole (6-disc diameter fovea-centered circle), peripheral (outside 6-disc diameter circle) and widefield far peripheral (outside 9-disc diameter circle); associations with clinical factors were evaluated with marginal beta regression models. Main Outcome MeasuresUWF-FA leakage index, calculated as the area with leakage divided by the analyzable retinal area. ResultsThe mean quantitative leakage index was 3.5% for panretinal, 6.6% for macular, 4.8% for posterior pole, 3.3% for peripheral and 2.8% for wide-field far peripheral retinal zones. Panretinal leakage was associated with DRSS (mean 2.2% for no to mild NPDR, 3.4% for moderate NPDR, 4.2% for moderately severe NPDR, 4.8% for severe NPDR and 5.1% for PDR; P<.001), HbA1c (3.2% for HbA1c <8% vs. 3.8% for HbA1c ≥8%; P=.01 for continuous HbA1c), visual acuity (3.3% for 20/25 or better vs. 4.7% for 20/32 or worse; continuous P<.001), and UWF-FA-PPL types of IRMA (4.3% vs. 3.3%; P=.005) or NVE (5.7% vs. 3.4%; P=.003). DRSS was also statistically significant for leakage within all retinal zones (P<.001); eyes with non-central DME versus no DME had higher mean leakage in the central macular (11.2% vs. 5.9%; P=0.005) and posterior pole regions (9.2% vs. 4.2%; P=.002). ConclusionQuantitative UWF-FA leakage analysis identified associations between leakage and DRSS, visual acuity, and presence of DME. In the future, quantitative UWF-FA leakage parameters may be explored as potential biomarkers for disease progression risk.

Nephrotoxicity of Intravenous Ganciclovir in Pediatric Hematopoietic Cell Transplant Recipients.

Associations between ganciclovir and severe nephrotoxicity are incompletely defined. Studies incorporating the time-varying nature of medication exposures and those that address confounding by indication are particularly scarce in children undergoing hematopoietic cell transplantation. We identified children undergoing hematopoietic cell transplantation in the Pediatric Health Information System database and tracked them for 1 year following transplantation. The primary exposure of interest was the use of ganciclovir, which was treated as a time-varying variable. Secondary exposures of interest included cidofovir, foscarnet, amphotericin B, aminoglycosides, vancomycin and calcineurin inhibitors. The primary outcome of interest was renal replacement therapy, which was assessed using marginal structural Cox proportional hazards regression model incorporating time-varying variables and inverse-probability-of-treatment weight. Of 17,924 children who underwent hematopoietic cell transplantation during the study period, 3078 (17.2%) had exposure to ganciclovir. In marginal structural Cox proportional hazards regression model incorporating time-varying variables and inverse-probability-of-treatment weight, ganciclovir was associated with an increased hazard of renal replacement therapy (adjusted hazard ratio: 1.84, 95% confidence interval: 1.22-2.76). Some of secondary exposures of interest, including cidofovir, amphotericin B and vancomycin, also were associated with renal replacement therapy. Intravenously administered ganciclovir is associated with renal dysfunction severe enough to require renal replacement therapy in pediatric hematopoietic cell transplant recipients. Ganciclovir should be used with caution and close monitoring. Approaches to mitigate the risks of nephrotoxicity should be investigated.

Risk of Recurrence in Acute Anterior Uveitis

PurposeTo examine the frequency of recurrence and identify risk factors for recurrence in patients with acute anterior uveitis (AAU). DesignRetrospective cohort study from a single tertiary ophthalmic clinical centre. ParticipantsAll subjects with AAU identified from a database of Inflammatory Eye Disease presenting to Te Whatu Ora (Auckland, New Zealand) between 2008 and 2021. MethodsData was collected retrospectively from chart review and electronic patient records for all patients during the study period. Rates of recurrence were reported using Kaplan Meier estimator. Multivariate analysis of risk factors for recurrence were calculated using a marginal Cox regression model. Main Outcome MeasuresThe primary outcome measure was disease recurrence. Secondary outcome measure was moderate vision loss (≤20/50). Results2763 eyes of 2092 subjects with AAU were studied, with a median follow up time of 8.9 years, and a total follow up of 19,794.9 eye-years. Recurrence occurred in the ipsilateral eye in 1258 eyes (45.5%) and in the contralateral eye in 522 eyes (27.3%). Rates of ipsilateral recurrence over ten years were 38.1% for idiopathic disease, 43.2% for HLAB27/inflammatory arthritis, and 44.9% for viral uveitis. On multivariate analysis the following were associated with increased risk of ipsilateral recurrence: older age (p<0.001); Māori ethnicity (p=0.006); Asian ethnicity (p<0.001); HLA-B27/inflammatory arthritis (p<0.001); viral uveitis (p=0.018). There was no association with gender, smoking, bilateral disease, or hypertensive uveitis. Rates of contralateral eye involvement were significantly lower than ipsilateral eye recurrence. Contralateral recurrence at ten years was 15.2% in idiopathic uveitis, 37.6% in HLAB27/inflammatory arthritis, and 2.0% in viral uveitis. Risk factors identified for contralateral eye involvement were Māori ethnicity (p=0.003), Pasifika (Pacific Islanders) ethnicity (p=0.021), HLAB27/inflammatory arthritis (p<0.001). Moderate vision loss (≤20/50) was present in 411 eyes (14.9%) at final follow up and was more common if time to first recurrence was shorter (p<0.001). ConclusionsApproximately half of patients with AAU will develop recurrence in the ipsilateral eye and a quarter will have recurrence in the contralateral eye. Patients with viral disease have the highest risk of ipsilateral recurrence and lowest risk of contralateral recurrence. Patients with risk factors for recurrence should be managed and counselled appropriately to minimise the risk of visual loss and complications of uveitis.

The effect of number of clusters and magnitude of within-cluster homogeneity in outcomes on the performance of four variance estimators for a marginal multivariable Cox regression model fit to clustered data in the context of observational research.

Researchers often estimate the association between the hazard of a time-to-event outcome and the characteristics of individuals and the clusters in which individuals are nested. Lin and Wei's robust variance estimator is often used with a Cox regression model fit to clustered data. Recently, alternative variance estimators have been proposed: the Fay-Graubard estimator, the Kauermann-Carroll estimator, and the Mancl-DeRouen estimator. Using Monte Carlo simulations, we found that, when fitting a marginal Cox regression model with both individual-level and cluster-level covariates: (i) in the presence of weak to moderate within-cluster homogeneity of outcomes, the Lin-Wei variance estimator can result in estimates of the SE with moderate bias when the number of clusters is fewer than 20-30, while in the presence of strong within-cluster homogeneity, it can result in biased estimation even when the number of clusters is as large as 100; (ii) when the number of clusters was less than approximately 20, the Fay-Graubard variance estimator tended to result in estimates of SE with the lowest bias; (iii) when the number of clusters exceeded approximately 20, the Mancl-DeRouen estimator tended to result in estimated standard errors with the lowest bias; (iv) the Mancl-DeRouen estimator used with a t-distribution tended to result in 95% confidence that had the best performance of the estimators; (v) when the magnitude of within-cluster homogeneity in outcomes was strong or very strong, all methods resulted in confidence intervals with lower than advertised coverage rates even when the number of clusters was very large.

In-hospital outcomes and postdischarge mortality in patients with acute coronary syndrome and atrial fibrillation

BackgroundIt is unclear whether advances in management of acute coronary syndrome (ACS) and introduction of novel oral anticoagulants have changed outcomes in patients with ACS with concomitant atrial fibrillation (AF). ObjectiveThis study aimed to examine the incidence of AF in patients admitted for ACS and to evaluate its association with adverse outcomes, given the recent advances in management of both diseases. MethodsNatural language processing search algorithms identified AF in patients admitted with ACS across 13 Northwell Health Hospitals from 2015 to 2021. Hierarchical generalized linear mixed modeling was used to assess the association between AF and in-hospital mortality, bleeding, and stroke outcomes; marginal Cox regression modeling was used to assess the association between AF and postdischarge mortality. ResultsOf 12,315 patients admitted for ACS, 3018 (24.5%) had AF with 1609 (53.3%) newly diagnosed. AF patients more commonly received anticoagulation with an oral anticoagulant (80.4% vs 12.3%) or heparin (61.9% vs 56.9%), had lengthier intensive care unit stay (72 vs 49 hours), and underwent fewer percutaneous coronary interventions (31.9% vs 53.1%). In-hospital bleeding, stroke, and mortality were higher in the AF group (15.3% vs 5.0%, 7.4% vs 2.4%, and 6.9% vs 2.1%, respectively). AF was an independent risk factor for all in-hospital outcomes (odds ratios of 2.5, 2.7, and 2.0 for bleeding, stroke, and mortality, respectively) as well as for postdischarge mortality (hazard ratio, 1.3; 95% CI, 1.2–1.5). ConclusionAF is present in 25% of ACS patients and increases risk of in-hospital and postdischarge adverse outcomes. Additional data are required to direct optimal management.

A Cluster Randomised Controlled Trial of a Targeted Distributed Toothpaste and Toothbrushing Programme.

The aim was to assess the effectiveness of a distributed, targeted toothbrush and toothpaste programme on referrals for tooth extraction under Dental General Anaesthetic (DGA), in children of high-risk families compared to usual care. A recruiter and assessor-blinded, clustered parallel randomised control trial (RCT). Families with one or more children aged between 3 and 10 years having undergone a DGA operation for extraction of carious teeth, were approached within hospitals in the North West of England. Families were randomised at the cluster level in a 1:1 ratio. All eligible children within the family consented to the study. The primary outcome was participant referral for a DGA 6-24-month post-randomisation. A total of 961 families (1,671 children) were randomised, 482 families (832 children) to the intervention, and 479 families (839 children) to the control group. Families (1,662 children, 955 families) were included in the final analysis (825 intervention, 837 control). Marginal regression models (generalised estimating equation approach) taking into account cluster membership were used to model the effectiveness of the intervention at 24 and 48 month follow-up, including the variables, age, sex, and IMD quintile. Seventy-six children (9.2%) in the intervention group had a DGA referral within 2 years compared to 57 children (6.8%) in the control group. The study found no effect of a clinically meaningful difference between the intervention group and usual care (risk ratio 1.36, 95% CI: 0.98-1.89) in reducing referral for DGA for a targeted postal toothpaste/toothbrush program in a contemporary, population with previous family experience of DGA residing in an area of high deprivation. The target of the intervention (families of children with a DGA) was the correct focus given the referrals observed over 2 and 4 years. The study can aid policymakers, local authorities and commissioners to understand repeat DGA within families and further need for intervention.

Continuity of mental disorders in children with chronic physical illness.

Data on the chronicity of mental disorder in children with chronic physical illness (CPI) are limited. We examined the prevalence and predictors of homotypic and heterotypic continuity of mental disorder in children with CPI. A sample of 263 children aged 2-16 years with physician-diagnosed CPI were recruited from outpatient clinics (e.g., dermatology, respiratory) at a Canadian pediatric academic hospital and followed for 24 months. Parent and child-reported mental disorders (mood, anxiety, behavioral, attention-deficit hyperactivity disorder [ADHD]) were assessed using the Mini International Neuropsychiatric Interview for Children and Adolescents at baseline, 6, 12, and 24 months. Marginal regression models were computed to identify clinical, parent, and demographic factors associated with mental comorbidity over time. Mental disorder was observed in 24-27% of children with CPI based on child reports and 35-39% based on parent reports. Parent-reported models revealed significant homotypic continuity for all mental disorders (ORs = 4.2-9.5), and heterotypic continuity between mood and anxiety disorders (OR = 2.2), ADHD and behavioral disorders (OR = 5.1), and behavioral and each mental disorder (ORs = 6.7-8.4). Child-reported models revealed significant homotypic continuity for mood (OR = 8.8) and anxiety disorder (OR = 6.0), and heterotypic continuity between anxiety and mood disorders (OR = 12.4). Child disability (ORs = 1.3-1.5) and parent psychopathology (ORs = 1.2-1.8) were the most consistent predictors of both child- and parent-reported mental disorder over time. Mental comorbidity was prevalent and persistent in children with CPI with homotypic and heterotypic continuity common across informants. Child disability and parent psychopathology may be priority targets within integrated family-centered models of care to prevent mental comorbidity in children with CPI.

Abstract P305: Room for Improved Secondary Prevention of Major Cardiovascular Events Among the Population With New Onset Diabetes: A Longitudinal Latent Class Trajectory Analysis

Background: After a diagnosis of diabetes, specialist physicians may play a key role in the secondary prevention of major cardiovascular events (MACE). Yet, trajectories of visits to specialists are heterogenous and their efficacy in the prevention of MACE remains unexplored. Goal: To assess whether trajectories of visits to specialists are associated with MACE among new cases of diabetes. Methods: Using the Quebec Integrated Chronic Disease Surveillance System, we identified new cases of diabetes ≥20 years old during fiscal year 2013, who had no prior history of MACE (ischemic cardiopathy, stroke, myocardial infarction or cardiovascular death). Firstly, individual trajectories according to the presence/absence of ≥1 ambulatory visit to a specialist (cardiologist, internist, endocrinologist) were compiled over consecutive 3-month periods up to 2 years following diagnosis. Patients with no visit were compiled in a “primary care only” group, while others were classified in groups using latent class growth analysis. Patients who had a MACE during this period were excluded. Secondly, the risk of MACE occuring after the 2 years following diagnosis up to December 31 st 2019 was compared between groups using a marginal Cox proportional hazards regression model, adjusted with inverse probability weighting and providing adjusted hazard ratio (aHR) with 95% confidence intervals (CI). Results: Among the 24,782 patients included, 5 groups were identified ( Figure 1 ). A total of 2,837 MACE occurred. Compared with the “primary care only group”, those who consulted a specialist were at higher risk of MACE (Regular/frequent visits: aHR: 1.50 [95% CI: 1.26 to 1.66]; Late visits: aHR: 1.41 [1.13 to 1.73]; Regular/sparce visits: 1.38 [1.27 to 1.51]; Early visits: 1.36 [1.19 to 1.54]), while no difference was observed between these groups. Conclusions: Although confounding by indication cannot be totally ruled out, these results may suggest room for improvement in the secondary prevention of MACE after a diabetes diagnosis.

Cumulative exposure to depressive symptoms and all-cause mortality among adults with HIV in Kenya, Nigeria, Tanzania, and Uganda.

We estimated the effects of cumulative exposure to depressive symptoms on risk of all-cause mortality among people with HIV (PWH) in four African countries. An analysis of prospective cohort data. The African Cohort Study (AFRICOS) is a prospective cohort of people receiving care at twelve clinics in Kenya, Nigeria, Tanzania, and Uganda. Every 6 months from January 2013 to May 2020, participants underwent laboratory monitoring, structured surveys, and assessment of depressive symptom severity using the Center for Epidemiologic Studies Depression Scale (CES-D). All-cause mortality was the outcome of interest. The predictor of interest was a time-updated measure of the percentage of days lived with depression (PDD). Marginal structural Cox proportional hazards regression models were used, adjusting for potential confounders including time-varying alcohol use, drug use, and viral load. Among 2520 enrolled participants, 1479 (59%) were women and the median age was 38 (interquartile range [IQR]: 32-46). At enrollment, 1438 (57%) were virally suppressed (<200 copies/ml) and 457 (18%) had CES-D at least 16, indicating possible depression. Across 9093 observed person-years, the median PDD was 0.7% (IQR: 0-5.9%) with 0.8 deaths per 100 person-years. Leading causes of death included cancer (18% of deaths) and accidents (14%). Models suggested that each 25% absolute increase in PDD was associated with a 69% increase in the risk of all-cause mortality (hazard ratio: 1.69; 95% confidence interval: 1.18-2.43). Cumulative exposure to depressive symptoms was substantially associated with the risk of mortality in this cohort of PWH in Africa.

The effect of the working correlation on fitting models to longitudinal data

AbstractWe present a detailed discussion of the theoretical properties of quadratic inference function estimators of the parameters in marginal linear regression models. We consider the effect of the choice of working correlation on fundamental questions including the existence of quadratic inference function estimators, their relationship with generalized estimating equations estimators, and the robustness and asymptotic relative efficiency of quadratic inference function and generalized estimating equations estimators. We show that the quadratic inference function estimators do not always exist and propose a way to handle this. We then show that they have unbounded influence functions and can be more or less asymptotically efficient than generalized estimating equations estimators. We also present empirical evidence to demonstrate these results. We conclude that the choice of working correlation can have surprisingly large effects.

Pregnancy outcomes in women with rheumatoid arthritis: an 11-year French nationwide study

BackgroundRheumatoid arthritis (RA) can affect women of childbearing age. The management of patients with RA during pregnancy has evolved over the past decades, especially with the availability of new therapeutic...

Catheter size and risk of short-term peripheral venous catheter-associated bloodstream infections: an observational study

ObjectivesShort-term peripheral venous catheter-associated bloodstream infections (PVC-associated BSI) are disregarded in the literature because of their relatively low incidence. No data are available on the association between PVC diameter size and the risk of PVC-associated BSI. MethodsUsing a prospective database, we performed an observational study at the University of Geneva Hospitals from 1 January 2020 to 31 December 2021, including all patients with a PVC. We used univariable and multivariable marginal Cox regression models for clustered data to investigate the association between catheter size and PVC-associated BSI. The main variable of interest ‘catheter size’ was forced into our multivariable models. Confounders, which are thought to influence the risk of PVC-associated BSI, were used as adjustment factors. ResultsA total of 206 804 PVCs were included. In all, 10 806 of 201 413 (5.4%), 80 274 of 201 413 (39.9%), 93 047 of 201 413 (46.2%) and 17 286 of 201 413 (8.6%) PVCs measured ≤16G, 18G, 20G and ≥22G, respectively. The univariable analysis showed that diameters of ≤16G were significantly associated with a higher risk of PVC-associated BSI (hazard ratio [HR] 4.52, 95% CI, 1.14–18.00). Multivariable models confirmed these results (HR 4.65, 95% CI, 1.19–18.20). Sensitivity analyses including PVC inserted only in 2021 (HR 4.80, 95% CI, 1.21–19.10), for dwell time >2 days (HR 3.67, 95% CI, 0.92–14.65) and only in adults (HR 3.97, 95% CI, 0.97–15.39) showed similar results. DiscussionLarger PVC size may increase the risk of PVC-associated BSI. Diameter size should be considered when selecting PVCs to reduce the burden of PVC-associated BSI.

Thrombosis recurrence and major bleeding in non-anticoagulated thrombotic antiphospholipid syndrome patients: Prospective study from antiphospholipid syndrome alliance for clinical trials and international networking (APS ACTION) clinical database and repository (“Registry”)

BackgroundLong-term anticoagulant therapy is generally recommended for thrombotic antiphospholipid syndrome (TAPS) patients, however it may be withdrawn or not introduced in routine practice. ObjectivesTo prospectively evaluate the risk of thrombosis recurrence and major bleeding in non-anticoagulated TAPS patients, compared to anticoagulated TAPS, and secondly, to identify different features between those two groups. Patients/MethodsUsing an international registry, we identified non-anticoagulated TAPS patients at baseline, and matched them with anticoagulated TAPS patients based on gender, age, type of previous thrombosis, and associated autoimmune disease. Thrombosis recurrence and major bleeding were prospectively analyzed using Kaplan-Meier method and compared using a marginal Cox's regression model. ResultsAs of June 2022, 94 (14 %) of the 662 TAPS patients were not anticoagulated; and 93 of them were matched with 181 anticoagulated TAPS patients (median follow-up 5 years [interquartile range 3 to 8]). The 5-year thrombosis recurrence and major bleeding rates were 12 % versus 10 %, and 6 % versus 7 %, respectively (hazard ratio [HR] 1.38, 95 % confidence interval [CI] 0.53 to 3.56, p = 0.50 and HR 0.53; 95 % CI 0.15 to 1.86; p = 0.32, respectively). Non-anticoagulated patients were more likely to receive antiplatelet therapy (p < 0.001), and less likely to have more than one previous thrombosis (p < 0.001) and lupus anticoagulant positivity (p = 0.01). ConclusionFourteen percent of the TAPS patients were not anticoagulated at recruitment. Their recurrent thrombosis risk did not differ compared to matched anticoagulated TAPS patients, supporting the pressing need for risk-stratified secondary thrombosis prevention trials in APS investigating strategies other than anticoagulation.

Epiretinal membrane in uveitis: Rate, visual prognosis, complications and surgical outcomes.

Epiretinal membrane (ERM) is a common finding in patients with uveitis that contributes to visual impairment. We describe the long-term visual acuity (VA) and morphometric progression in patients with uveitis and epiretinal membrane (ERM). Retrospective cohort study of patients with uveitic ERM from a tertiary centre database. Multivariate analysis of risk factors for ERM progression was calculated using a marginal Cox regression model to estimate hazard ratios (HR). Two hundred and sixteen eyes (4%) of a total 5450 eyes with uveitis were identified to have an ERM. The most common diagnosis was idiopathic uveitis in 45 patients (28.7%), followed by sarcoidosis in 21 (13.4%), HLAB27-related uveitis in 15 (9.6%) and toxoplasmosis in 15 (9.6%). Risk factors for ERM development include age (HR 1.03), intermediate uveitis (HR 2.33), posterior uveitis (HR 1.53) and ERM fellow eye (HR 18.28). Anterior uveitis (HR 0.53) and alternating disease (HR 0.53) were protective. Median VA was 20/40 at diagnosis of ERM and 20/40 at final follow up. Progression of ERM grade occurred in 17 eyes (7.9%) during the study period. ERM peel was performed in 44 eyes (20.4%). Median VA was 20/60 and 20/40 at baseline and 12 months after surgery, respectively. Improvement in visual acuity occurred in 23 eyes (60.5%) following surgery. In addition to intermediate and posterior uveitis, fellow eye involvement is a strong risk factor for ERM development. In treated uveitis, the majority maintain their long-term vision and rates of ERM progression are low.

Effects of iron-based phosphate binders on mortality and cardiovascular events in patients receiving maintenance dialysis

Phosphate binders are the main treatment for hyperphosphatemia in patients with chronic kidney disease, and iron-based phosphate binders have been used with increasing frequency in recent years. This study examined the association of the use of iron-based, rather than non-iron-based, phosphate binders with the incidence of cardiovascular events, in a real-world setting. We used data from a cohort comprising representative adult patients on maintenance hemodialysis in Japan. The exposure of interest was the time-varying use of phosphate binders, classified into “iron-based”, “only non-iron-based”, and “no use”. The primary outcome was a composite of cardiovascular events and all-cause deaths. A marginal structural Cox regression model was used to deal with possible time-dependent confounding. Of the 2247 patients from 58 hemodialysis facilities, iron-based and only non-iron-based phosphate binders were used in 328 (15%) and 1360 (61%), respectively, at baseline. Hazard ratios (95% confidence intervals) for iron-based and non-iron-based phosphate binders versus no use of phosphate binders were 0.35 (0.24, 0.52) and 0.44 (0.33, 0.58), respectively. The hazard ratio for iron-based relative to non-iron-based phosphate binders was 0.81 (0.58, 1.13), which was not statistically significant. Further studies are warranted to elucidate whether the use of iron-based phosphate binders reduces the event rate.

Foreign investors, rebalancing trades, and increases in U.S.-Japan stock market correlations

ABSTRACT Foreign investors’ transaction volume in the Tokyo Stock Exchange has grown steadily in the past three decades, and Japanese stocks have become a familiar instrument for international diversification. Rebalancing trades in a local national market by foreign institutional investors holding multi-country asset portfolios, often heavily represented by U.S. stocks, amplify the national market’s stock index co-movements with the U.S. This paper examines the extent to which greater participation of foreign investors is associated with increases in the unconditional correlation of daily returns between the U.S. (S&P 500) and Japan (TOPIX). A Gaussian copula marginal regression model is applied to the monthly series of unconditional correlations. We find that the growth in foreign investors’ transaction share of the Tokyo market’s turnover approximately accounts for the rise in U.S.-Japan correlations for 1990–2019. Foreign investors’ trades improve the informational efficiency of local national markets. Increased correlations lead to smaller potential gains from international diversification, however.

A marginal structural model to estimate the effect of antidepressant medication treatment on major cardiovascular events among people with post-traumatic stress disorder.

Previous evidence on antidepressant medication and cardiovascular disease (CVD) among patients with posttraumatic stress disorder (PTSD) has been inconclusive. We estimated the association between antidepressant medication and CVD by applying a marginal structural model. We analyzed medical utilization records of 27 170 people with PTSD without prior major cardiovascular events in the Korean National Health Insurance Database (NHID). PTSD and CVD were defined in accordance with the recorded ICD-10 diagnostic codes. We acquired information on antidepressant use from the NHID and categorized them by medication type. A composite major adverse cardiovascular events (MACE) outcome was defined as coronary artery disease with revascularization, ischaemic stroke, and/or haemorrhagic stroke. We used inverse probability of treatment weighting to estimate the parameters of a marginal structural discrete-time survival analysis regression model, comparing the resulting estimates to those derived from traditional time-fixed and time-varying Cox proportional hazards regression. We calculated cumulative daily defined doses to test for a dose-response relationship. People exposed to antidepressants showed a higher hazard of MACE [hazard ratio (HR) 1.34, 95% confidence interval (CI) 1.18-1.53]. The estimated effects were strongest for selective serotonin reuptake inhibitors (HR 1.24, 95% CI 1.08-1.44) and TCAs (HR 1.33, 95% CI 1.13-1.56). Exposure to serotonin-norepinephrine reuptake inhibitors did not appear to increase the risk of MACE. People exposed to higher doses of antidepressants showed higher risk of MACE. In a national cohort of people with PTSD, exposure to antidepressant medications increased the risk of MACE in a dose-response fashion.

Factors Associated With Neuroradiologic Diagnostic Errors at a Large Tertiary-Care Academic Medical Center: A Case-Control Study.

BACKGROUND. Numerous studies have explored factors associated with diagnostic errors in neuroradiology; however, large-scale multivariable analyses are lacking. OBJECTIVE. The purpose of this study was to evaluate associations of interpretation time, shift volume, care setting, day of week, and trainee participation with diagnostic errors by neuroradiologists at a large academic medical center. METHODS. This retrospective case-control study using a large tertiary-care academic medical center's neuroradiology quality assurance database evaluated CT and MRI examinations for which neuroradiologists had assigned RADPEER scores. The database was searched from January 2014 through March 2020 for examinations without (RADPEER score of 1) or with (RADPEER scores of 2a, 2b, 3a, 3b, or 4) diagnostic error. For each examination with error, two examinations without error were randomly selected (unless only one examination could be identified) and matched by interpreting radiologist and examination type to form case and control groups. Marginal mixed-effects logistic regression models were used to assess associations of diagnostic error with interpretation time (number of minutes since the immediately preceding report's completion), shift volume (number of examinations interpreted during the shift), emergency/inpatient setting, weekend interpretation, and trainee participation in interpretation. RESULTS. The case group included 564 examinations in 564 patients (mean age, 50.0 ± 25.0 [SD] years; 309 men, 255 women); the control group included 1019 examinations in 1019 patients (mean age, 52.5 ± 23.2 years; 540 men, 479 women). In the case versus control group, mean interpretation time was 16.3 ± 17.2 [SD] minutes versus 14.8 ± 16.7 minutes; mean shift volume was 50.0 ± 22.1 [SD] examinations versus 45.4 ± 22.9 examinations. In univariable models, diagnostic error was associated with shift volume (OR = 1.22, p < .001) and weekend interpretation (OR = 1.60, p < .001) but not interpretation time, emergency/inpatient setting, or trainee participation (p > .05). However, in multivariable models, diagnostic error was independently associated with interpretation time (OR = 1.18, p = .003), shift volume (OR = 1.27, p < .001), and weekend interpretation (OR = 1.69, p = .02). In subanalysis, diagnostic error showed independent associations on weekdays with interpretation time (OR = 1.18, p = .003) and shift volume (OR = 1.27, p < .001); such associations were not observed on weekends (interpretation time: p = .62; shift volume: p = .58). CONCLUSION. Diagnostic errors in neuroradiology were associated with longer interpretation times, higher shift volumes, and weekend interpretation. CLINICAL IMPACT. These findings should be considered when designing work-flow-related interventions seeking to reduce neuroradiology interpretation errors.