P0846ESA HYPORESPOSIVENESS AND CLINICAL OUTCOMES DURING TREATMENT WITH EPOETIN BETA PEGOL IN HEMODIALYSIS PATIENTS: A MULTICENTER PROSPECTIVE STUDY; PARAMOUNT-HD STUDY

Abstract Background and Aims Hemodialysis (HD) patients hyporesponsive to erythropoiesis stimulating agents (ESAs) were reported to have poor prognosis. However, little is known regarding the association between the hyporesponsiveness to CERA and the types of outcome in HD patients. Moreover, the effect of on-line HDF on hyporesponsiveness to CERA has not been evaluated so far. Method In this multicenter prospective study, we enrolled 4034 maintenance HD patients receiving any kinds of ESA. Prior ESA was changed to CERA in all patients. We studied the association between erythropoietin resistance index (ERI) at 6-month after the change to CERA (baseline ERI) and such outcomes as cardiovascular events and/or mortality using Cox proportional hazards models (landmark analyses). ERI was defined as monthly CERA dose divided by hemoglobin and dry weight. Just before the enrollment of the patients, iron-based phosphate binders became available and on-line hemodiafiltration (HDF) began to be reimbursed in Japan, therefore, we examined whether oral iron-containing drugs and on-line HDF had some effects on the serial trend of ERI by mixed effects model with time-dependent ERI as a dependent variable. When ERI is found to be improved by these changes in practice patterns, we further studied the effect of time-dependent ERI on such outcomes as cardiovascular events, mortality, death due to cancer, and death due to infection by using marginal structural models to eradicate time-dependent confounding by iron parameters, C-reactive protein, iron-containing drugs, and HDF. Missing values were imputed by multiple imputations. Results Mean age was 65.9 years and 43.1% of patients had diabetes. The median dialysis vintage and observation period was 5.0 years and 22.1 months, respectively. The percentage of patients receiving oral iron-containing drugs increased from 11.1% at baseline to 25.0% at 24-month. As a result, mean TSAT level increased from 24.5% to 27.4% at 24-month. The percentage of patients on on-line HDF also increased from 13.5% to 22.6%. ERI gradually decreased as time went by with great improvement especially in patients with highest quintile of ERI (Q5). Mixed effects model with time-dependent ERI as a dependent variable showed that introduction of iron-containing drugs and on-line HDF had improved ERI significantly. The landmark analyses including 3001 patients failed to show significant associations between baseline ERI quintile and cardiovascular events or mortality. We only found that highest quintile of baseline ERI (Q5) was associated with significantly higher composite events of mortality and cardiovascular events as compared to the lowest quintile (Q1) (Hazard ratio [HR], 1.56; 95% CI; 1.04-2.32). However, marginal structural models showed that time-dependent ERI Q5 was significantly associated with higher cardiovascular event rate as compared to Q1 (HR, 2.11; 95% CI; 1.31-3.38). Trend toward higher rate of mortality with the increase in time-dependent ERI quintile was also observed (HR of Q5, 3.07; 95% CI; 1.95-4.83). Similar but stronger relationships were observed for death due to infection (HR of Q5, 6.70; 95% CI; 1.89-23.77) and death due to cancer (HR of Q5, 15.08; 95% CI; 4.08-55.74). Conclusion The prevailing use of iron-containing drugs and on-line HDF has improved hyporesponsiveness to CERA in Japan. Therefore, baseline ERI at 6-month did not predict subsequent cardiovascular events or death. However, high time-dependent ERI was a predictor of cardiovascular events, death due to infection, and death due to cancer as well as all-cause mortality. Strong association of time-dependent ERI was observed especially with death due to cancer.

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A joint modeling approach for longitudinal microbiome data improves ability to detect microbiome associations with disease

PLoS Computational Biology ◽

10.1371/journal.pcbi.1008473 ◽

2020 ◽

Vol 16 (12) ◽

pp. e1008473

Author(s):

Pamela N. Luna ◽

Jonathan M. Mansbach ◽

Chad A. Shaw

Keyword(s):

Joint Modeling ◽

Mixed Effects ◽

Mixed Effects Model ◽

Time Dependent ◽

Time To Event ◽

Modeling Framework ◽

Microbial Composition ◽

Disease Outcomes ◽

Microbiome Data ◽

Over Time

Changes in the composition of the microbiome over time are associated with myriad human illnesses. Unfortunately, the lack of analytic techniques has hindered researchers’ ability to quantify the association between longitudinal microbial composition and time-to-event outcomes. Prior methodological work developed the joint model for longitudinal and time-to-event data to incorporate time-dependent biomarker covariates into the hazard regression approach to disease outcomes. The original implementation of this joint modeling approach employed a linear mixed effects model to represent the time-dependent covariates. However, when the distribution of the time-dependent covariate is non-Gaussian, as is the case with microbial abundances, researchers require different statistical methodology. We present a joint modeling framework that uses a negative binomial mixed effects model to determine longitudinal taxon abundances. We incorporate these modeled microbial abundances into a hazard function with a parameterization that not only accounts for the proportional nature of microbiome data, but also generates biologically interpretable results. Herein we demonstrate the performance improvements of our approach over existing alternatives via simulation as well as a previously published longitudinal dataset studying the microbiome during pregnancy. The results demonstrate that our joint modeling framework for longitudinal microbiome count data provides a powerful methodology to uncover associations between changes in microbial abundances over time and the onset of disease. This method offers the potential to equip researchers with a deeper understanding of the associations between longitudinal microbial composition changes and disease outcomes. This new approach could potentially lead to new diagnostic biomarkers or inform clinical interventions to help prevent or treat disease.

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Editorial: Observational Studies, Time-Dependent Confounding, and Marginal Structural Models

Arthritis & Rheumatology ◽

10.1002/art.38931 ◽

2015 ◽

Vol 67 (3) ◽

pp. 609-611 ◽

Cited By ~ 3

Author(s):

Charles E. McCulloch

Keyword(s):

Observational Studies ◽

Structural Models ◽

Time Dependent ◽

Marginal Structural Models

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Simulating from marginal structural models with time-dependent confounding

Statistics in Medicine ◽

10.1002/sim.5472 ◽

2012 ◽

Vol 31 (30) ◽

pp. 4190-4206 ◽

Cited By ~ 17

Author(s):

W.G. Havercroft ◽

V. Didelez

Keyword(s):

Structural Models ◽

Time Dependent ◽

Marginal Structural Models

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Introduction to Time-dependent Confounders and Marginal Structural Models

Annals of Clinical Epidemiology ◽

10.37737/ace.3.2_37 ◽

2021 ◽

Vol 3 (2) ◽

pp. 37-45

Author(s):

Asuka Tsuchiya

Keyword(s):

Structural Models ◽

Time Dependent ◽

Marginal Structural Models

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Peer Review of Reviewers: The Author’s Perspective

Publications ◽

10.3390/publications7010001 ◽

2018 ◽

Vol 7 (1) ◽

pp. 1 ◽

Cited By ~ 5

Author(s):

Ivana Drvenica ◽

Giangiacomo Bravo ◽

Lucija Vejmelka ◽

Aleksandar Dekanski ◽

Olgica Nedić

Keyword(s):

Review Process ◽

Qualitative Content Analysis ◽

Ordinary Least Squares ◽

Mixed Effects ◽

Mixed Effects Model ◽

Open Questions ◽

Two Factors ◽

On Line ◽

Editorial Decision ◽

Line Survey

The aim of this study was to investigate the opinion of authors on the overall quality and effectiveness of reviewers’ contributions to reviewed papers. We employed an on-line survey of thirteen journals which publish articles in the field of life, social or technological sciences. Responses received from 193 authors were analysed using a mixed-effects model in order to determine factors deemed the most important in the authors’ evaluation of the reviewers. Qualitative content analysis of the responses to open questions was performed as well. The mixed-effects model revealed that the authors’ assessment of the competence of referees strongly depended on the final editorial decision and that the speed of the review process was influential as well. In Ordinary Least Squares (OLS) analysis on seven questions detailing authors’ opinions, perception of review speed remained a significant predictor of the assessment. In addition, both the perceived competence and helpfulness of the reviewers significantly and positively affected the authors’ evaluation. New models were used to re-check the value of these two factors and it was confirmed that the assessment of the competence of reviewers strongly depended on the final editorial decision.

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Association of Blood Pressure with Cardiovascular Outcome and Mortality: Results from the KNOW-CKD Study

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab257 ◽

2021 ◽

Author(s):

Jee Young Lee ◽

Jung Tak Park ◽

Young Su Joo ◽

Changhyun Lee ◽

Hae-Ryong Yun ◽

...

Keyword(s):

Cardiovascular Events ◽

Structural Models ◽

Cardiovascular Outcome ◽

Marginal Structural Models ◽

Potential Hazard ◽

Composite Outcome ◽

Hazard Ratios ◽

Adverse Cardiovascular Outcome ◽

Primary Composite Outcome

Abstract Background Optimal BP control is a major therapeutic strategy to reduce adverse cardiovascular events and mortality in patients with CKD. We studied the association of BP with adverse cardiovascular outcome and all-cause death in patients with CKD. Methods Among 2,238 participants from the KoreaN cohort study for Outcome in patients With CKD, 2,226 patients with baseline BP measurements were enrolled. Main predictor was SBP categorized by 5 levels: <110, 110-119, 120-129, 130-139, and ≥140 mmHg. Primary endpoint was a composite outcome of all-cause death or incident cardiovascular events. We primarily used marginal structural models using averaged and the most recent time-updated SBPs. Results During a median follow-up of 10233.79 person-years (median 4.60 years), the primary composite outcome occurred in 240 (10.8%) participants, with a corresponding incidence rate of 23.5 (95% CI, 20.7–26.6) per 1,000 patient-years. Marginal structural models with averaged SBP showed a U-shaped relationship with the primary outcome. Compared to time-updated SBP of 110–119 mmHg, hazard ratios (95% CI) for <110, 120–129, 130–139, and ≥140 mmHg were 2.47 (1.48–4.11), 1.29 (0.80–2.08), 2.15 (1.26–3.69), and 2.19 (1.19–4.01), respectively. Marginal structural models with the most recent SBP also showed similar findings. Conclusions In Korean patients with CKD, there was a U-shaped association of SBP with the risk of adverse clinical outcome. Our findings highlight the importance of BP control and suggest a potential hazard of SBP <110 mmHg.

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