SUMMARY
Mediation analysis explores the degree to which an exposure's effect on an outcome is diverted through a mediating variable. We describe a classical regression framework for conducting ...mediation analyses in which estimates of causal mediation effects and their variance are obtained from the fit of a single regression model. The vector of changes in exposure pathway coefficients, which we named the essential mediation components (EMCs), is used to estimate standard causal mediation effects. Because these effects are often simple functions of the EMCs, an analytical expression for their model-based variance follows directly. Given this formula, it is instructive to revisit the performance of routinely used variance approximations (e.g., delta method and resampling methods). Requiring the fit of only one model reduces the computation time required for complex mediation analyses and permits the use of a rich suite of regression tools that are not easily implemented on a system of three equations, as would be required in the Baron-Kenny framework. Using data from the BRAIN-ICU study, we provide examples to illustrate the advantages of this framework and compare it with the existing approaches.
OBJECTIVES:Acute kidney injury frequently complicates critical illness and is associated with high morbidity and mortality. Frailty is common in critical illness survivors, but little is known about ...the impact of acute kidney injury. We examined the association of acute kidney injury and frailty within a year of hospital discharge in survivors of critical illness.
DESIGN:Secondary analysis of a prospective cohort study.
SETTING:Medical/surgical ICU of a U.S. tertiary care medical center.
PATIENTS:Three hundred seventeen participants with respiratory failure and/or shock.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:Acute kidney injury was determined using Kidney Disease Improving Global Outcomes stages. Clinical frailty status was determined using the Clinical Frailty Scale at 3 and 12 months following discharge. Covariates included mean ICU Sequential Organ Failure Assessment score and Acute Physiology and Chronic Health Evaluation II score as well as baseline comorbidity (i.e., Charlson Comorbidity Index), kidney function, and Clinical Frailty Scale score. Of 317 patients, 243 (77%) had acute kidney injury and one in four patients with acute kidney injury was frail at baseline. In adjusted models, acute kidney injury stages 1, 2, and 3 were associated with higher frailty scores at 3 months (odds ratio, 1.92; 95% CI, 1.14–3.24; odds ratio, 2.40; 95% CI, 1.31–4.42; and odds ratio, 4.41; 95% CI, 2.20–8.82, respectively). At 12 months, a similar association of acute kidney injury stages 1, 2, and 3 and higher Clinical Frailty Scale score was noted (odds ratio, 1.87; 95% CI, 1.11–3.14; odds ratio, 1.81; 95% CI, 0.94–3.48; and odds ratio, 2.76; 95% CI, 1.34–5.66, respectively). In supplemental and sensitivity analyses, analogous patterns of association were observed.
CONCLUSIONS:Acute kidney injury in survivors of critical illness predicted worse frailty status 3 and 12 months postdischarge. These findings have important implications on clinical decision making among acute kidney injury survivors and underscore the need to understand the drivers of frailty to improve patient-centered outcomes.
We introduce and extend the classical regression framework for conducting mediation analysis from the fit of only one model. Using the essential mediation components (EMCs) allows us to estimate ...causal mediation effects and their analytical variance. This single-equation approach reduces computation time and permits the use of a rich suite of regression tools that are not easily implemented on a system of three equations. Additionally, we extend this framework to non-nested mediation systems, provide a joint measure of mediation for complex mediation hypotheses, propose new visualizations for mediation effects, and explain why estimates of the total effect may differ depending on the approach used. Using data from social science studies, we also provide extensive illustrations of the usefulness of this framework and its advantages over traditional approaches to mediation analysis. The example data are freely available for download online and we include the R code necessary to reproduce our results.
Recent trials have suggested use of balanced crystalloids may decrease the incidence of major adverse kidney events compared to saline in critically ill adults. The effect of crystalloid composition ...on biomarkers of early acute kidney injury remains unknown.
From February 15 to July 15, 2016, we conducted an ancillary study to the Isotonic Solutions and Major Adverse Renal Events Trial (SMART) comparing the effect of balanced crystalloids versus saline on urinary levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) among 261 consecutively-enrolled critically ill adults admitted from the emergency department to the medical ICU. After informed consent, we collected urine 36 ± 12 h after hospital admission and measured NGAL and KIM-1 levels using commercially available ELISAs. Levels of NGAL and KIM-1 at 36 ± 12 h were compared between patients assigned to balanced crystalloids versus saline using a Mann-Whitney U test.
The 131 patients (50.2%) assigned to the balanced crystalloid group and the 130 patients (49.8%) assigned to the saline group were similar at baseline. Urinary NGAL levels were significantly lower in the balanced crystalloid group (median, 39.4 ng/mg IQR 9.9 to 133.2) compared with the saline group (median, 64.4 ng/mg IQR 27.6 to 339.9) (P < 0.001). Urinary KIM-1 levels did not significantly differ between the balanced crystalloid group (median, 2.7 ng/mg IQR 1.5 to 4.9) and the saline group (median, 2.4 ng/mg IQR 1.3 to 5.0) (P = 0.36).
In this ancillary analysis of a clinical trial comparing balanced crystalloids to saline among critically ill adults, balanced crystalloids were associated with lower urinary concentrations of NGAL and similar urinary concentrations of KIM-1, compared with saline. These results suggest only a modest reduction in early biomarkers of acute kidney injury with use of balanced crystalloids compared with saline.
ClinicalTrials.gov number: NCT02444988 . Date registered: May 15, 2015.
A previous efficacy trial found benefit from inhaled budesonide for COVID-19 in patients not admitted to hospital, but effectiveness in high-risk individuals is unknown. We aimed to establish whether ...inhaled budesonide reduces time to recovery and COVID-19-related hospital admissions or deaths among people at high risk of complications in the community.
PRINCIPLE is a multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial done remotely from a central trial site and at primary care centres in the UK. Eligible participants were aged 65 years or older or 50 years or older with comorbidities, and unwell for up to 14 days with suspected COVID-19 but not admitted to hospital. Participants were randomly assigned to usual care, usual care plus inhaled budesonide (800 μg twice daily for 14 days), or usual care plus other interventions, and followed up for 28 days. Participants were aware of group assignment. The coprimary endpoints are time to first self-reported recovery and hospital admission or death related to COVID-19, within 28 days, analysed using Bayesian models. The primary analysis population included all eligible SARS-CoV-2-positive participants randomly assigned to budesonide, usual care, and other interventions, from the start of the platform trial until the budesonide group was closed. This trial is registered at the ISRCTN registry (ISRCTN86534580) and is ongoing.
The trial began enrolment on April 2, 2020, with randomisation to budesonide from Nov 27, 2020, until March 31, 2021, when the prespecified time to recovery superiority criterion was met. 4700 participants were randomly assigned to budesonide (n=1073), usual care alone (n=1988), or other treatments (n=1639). The primary analysis model includes 2530 SARS-CoV-2-positive participants, with 787 in the budesonide group, 1069 in the usual care group, and 974 receiving other treatments. There was a benefit in time to first self-reported recovery of an estimated 2·94 days (95% Bayesian credible interval BCI 1·19 to 5·12) in the budesonide group versus the usual care group (11·8 days 95% BCI 10·0 to 14·1 vs 14·7 days 12·3 to 18·0; hazard ratio 1·21 95% BCI 1·08 to 1·36), with a probability of superiority greater than 0·999, meeting the prespecified superiority threshold of 0·99. For the hospital admission or death outcome, the estimated rate was 6·8% (95% BCI 4·1 to 10·2) in the budesonide group versus 8·8% (5·5 to 12·7) in the usual care group (estimated absolute difference 2·0% 95% BCI –0·2 to 4·5; odds ratio 0·75 95% BCI 0·55 to 1·03), with a probability of superiority 0·963, below the prespecified superiority threshold of 0·975. Two participants in the budesonide group and four in the usual care group had serious adverse events (hospital admissions unrelated to COVID-19).
Inhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications.
National Institute of Health Research and United Kingdom Research Innovation.
In a randomized trial, patients with severe Covid-19 were assigned to receive either therapeutic-dose anticoagulation or usual-care pharmacologic thromboprophylaxis. At 21 days, therapeutic-dose ...anticoagulation did not improve hospital survival or the number of days free of cardiovascular or respiratory organ support.
In a randomized trial, patients with moderately severe Covid-19 were assigned to receive either therapeutic-dose anticoagulation or usual-care thromboprophylaxis. At 21 days, therapeutic-dose ...anticoagulation resulted in a higher probability of survival until hospital discharge without organ support.
The interleukin-6 receptor blockers tocilizumab and sarilumab were tested against standard care in a randomized trial involving patients newly admitted to the intensive care unit and requiring ...respiratory or blood-pressure support. The median number of organ support–free days was 10 with tocilizumab, 11 with sarilumab, and 0 with standard care.
The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of ...morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population.
PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older—or aged 18 years or older with relevant comorbidities—and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031.
Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 95% Bayesian credible interval 0·81–1·41; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir.
Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community.
UK National Institute for Health and Care Research
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