Latent class analysis is a probabilistic modeling algorithm that allows clustering of data and statistical inference. There has been a recent upsurge in the application of latent class analysis in ...the fields of critical care, respiratory medicine, and beyond. In this review, we present a brief overview of the principles behind latent class analysis. Furthermore, in a stepwise manner, we outline the key processes necessary to perform latent class analysis including some of the challenges and pitfalls faced at each of these steps. The review provides a one-stop shop for investigators seeking to apply latent class analysis to their data.
Purpose
Using latent class analysis (LCA), we have consistently identified two distinct subphenotypes in four randomized controlled trial cohorts of ARDS. One subphenotype has hyper-inflammatory ...characteristics and is associated with worse clinical outcomes. Further, within three negative clinical trials, we observed differential treatment response by subphenotype to randomly assigned interventions. The main purpose of this study was to identify ARDS subphenotypes in a contemporary NHLBI Network trial of infection-associated ARDS (SAILS) using LCA and to test for differential treatment response to rosuvastatin therapy in the subphenotypes.
Methods
LCA models were constructed using a combination of biomarker and clinical data at baseline in the SAILS study (
n
= 745). LCA modeling was then repeated using an expanded set of clinical class-defining variables. Subphenotypes were tested for differential treatment response to rosuvastatin.
Results
The two-class LCA model best fit the population. Forty percent of the patients were classified as the “hyper-inflammatory” subphenotype. Including additional clinical variables in the LCA models did not identify new classes. Mortality at day 60 and day 90 was higher in the hyper-inflammatory subphenotype. No differences in outcome were observed between hyper-inflammatory patients randomized to rosuvastatin therapy versus placebo.
Conclusions
LCA using a two-subphenotype model best described the SAILS population. The subphenotypes have features consistent with those previously reported in four other cohorts. Addition of new class-defining variables in the LCA model did not yield additional subphenotypes. No treatment effect was observed with rosuvastatin. These findings further validate the presence of two subphenotypes and demonstrate their utility for patient stratification in ARDS.
This study examined the relationship between leukocyte telomere length (LTL), a marker of cell aging, and psychiatric disorders in adults compared with controls using meta-analytic methods.
Data were ...abstracted from studies examining the relationship between LTL and adult psychiatric disorders. In addition to an overall estimate of effect size, subgroup analyses and meta-regression were performed to examine whether covariates (including psychiatric diagnoses) moderated the estimate.
A significant overall effect size showing LTL shortening was found across all psychiatric disorders (Hedge g = -0.50, p < .001). Subgroup analyses did not demonstrate significant differences in effect size based on individual covariates (psychiatric disorder, sex, age, or assay method). The meta-regression indicated that although type of disorder and, likely, age moderate the overall effect size, the heterogeneity between studies could not be explained by a model that included these variables as well as sex and assay method. Although not significantly different, posttraumatic stress disorder, anxiety disorders, and depressive disorders had comparatively larger effect sizes (-1.27, -0.53, and -0.55), and psychotic and bipolar disorders had comparatively smaller ones (-0.23 and -0.26).
We observed a robust effect size of LTL shortening for psychiatric disorders as a whole compared with controls. The results were less straightforward regarding relative differences in the strength of this association by specific disorder. Future studies should focus on mechanisms explaining accelerated cell aging with psychiatric illness, defining directions (if any) of causality and elucidating possible differences in this association between disorders.
Alveolar epithelial-capillary barrier disruption is a hallmark of acute respiratory distress syndrome (ARDS). Contribution of mitochondrial dysfunction to the compromised alveolar-capillary barrier ...in ARDS remains unclear. Mesenchymal stromal cells-derived extracellular vesicles (MSC-EVs) are considered as a cell-free therapy for ARDS. Mitochondrial transfer was shown to be important for the therapeutic effects of MSCs and MSC-EVs. Here we investigated the contribution of mitochondrial dysfunction to the injury of alveolar epithelial and endothelial barriers in ARDS and the ability of MSC-EVs to modulate alveolar-capillary barrier integrity through mitochondrial transfer.Primary human small airway epithelial and pulmonary microvascular endothelial cells and human precision cut lung slices (PCLSs) were stimulated with endotoxin or plasma samples from patients with ARDS and treated with MSC-EVs, barrier properties and mitochondrial functions were evaluated. Lipopolysaccharide (LPS)-injured mice were treated with MSC-EVs and degree of lung injury and mitochondrial respiration of the lung tissue were assessed.Inflammatory stimulation resulted in increased permeability coupled with pronounced mitochondrial dysfunction in both types of primary cells and PCLSs. Extracellular vesicles derived from normal MSCs restored barrier integrity and normal levels of oxidative phosphorylation while an extracellular vesicles preparation which did not contain mitochondria was not effective.
, presence of mitochondria was critical for extracellular vesicles ability to reduce lung injury and restore mitochondrial respiration in the lung tissue.In the ARDS environment, MSC-EVs improve alveolar-capillary barrier properties through restoration of mitochondrial functions at least partially
mitochondrial transfer.
Abstract
Introduction
This study examined the effects of experimentally manipulated social media exposure on adolescents’ willingness and intention to use e-cigarettes.
Aims and Methods
Participants ...were 135 adolescents of age 13–18 (52.6% female, mean age = 15.3) in California. Participants viewed six social media posts online in a 2 (post source: peer or advertisement) × 2 (e-cigarette content exposure: heavy or light) between-subjects design. Analyses were weighted to population benchmarks. We examined adolescents’ beliefs, willingness, and intention to use e-cigarettes in association with social media use intensity in daily life and with experimentally manipulated exposure to social media posts that varied by source (peer or advertisement) and content (e-cigarette heavy or light).
Results
Greater social media use in daily life was associated with greater willingness and intention to use e-cigarettes and more positive attitudes, greater perceived norms, and lower perceived danger of e-cigarette use (all p-values <.01). In tests of the experimental exposures, heavy (vs. light) e-cigarette content resulted in greater intention (p = .049) to use e-cigarettes and more positive attitudes (p = .019). Viewing advertisements (vs. peer-generated posts) resulted in greater willingness and intention (p-values <.01) to use e-cigarettes, more positive attitudes (p = .003), and greater norm perceptions (p = .009). The interaction effect of post source by post content was not significant for any of the outcomes (all p-values >.529).
Conclusions
Greater social media use and heavier exposure to advertisements and e-cigarette content in social media posts are associated with a greater risk for e-cigarette use among adolescents. Regulatory action is needed to prohibit sponsored e-cigarette content on social media platforms used by youth.
Implications
Adolescents who use social media intensely may be at higher risk for e-cigarette use. Even brief exposure to e-cigarette content on social media was associated with greater intention to use and more positive attitudes toward e-cigarettes. Regulatory action should be taken to prohibit sponsored e-cigarette content on social media used by young people, including posts by influencers who appeal to young people.
Using latent class analysis (LCA) in five randomised controlled trial (RCT) cohorts, two distinct phenotypes of acute respiratory distress syndrome (ARDS) have been identified: hypoinflammatory and ...hyperinflammatory. The phenotypes are associated with differential outcomes and treatment response. The objective of this study was to develop parsimonious models for phenotype identification that could be accurate and feasible to use in the clinical setting.
In this retrospective study, three RCT cohorts from the National Lung, Heart, and Blood Institute ARDS Network (ARMA, ALVEOLI, and FACTT) were used as the derivation dataset (n=2022), from which the machine learning and logistic regression classifer models were derived, and a fourth (SAILS; n=715) from the same network was used as the validation test set. LCA-derived phenotypes in all of these cohorts served as the reference standard. Machine-learning algorithms (random forest, bootstrapped aggregating, and least absolute shrinkage and selection operator) were used to select a maximum of six important classifier variables, which were then used to develop nested logistic regression models. Only cases with complete biomarker data in the derivation dataset were used for variable selection. The best logistic regression models based on parsimony and predictive accuracy were then evaluated in the validation test set. Finally, the models' prognostic validity was tested in two external ARDS clinical trial datasets (START and HARP-2) by assessing mortality at days 28, 60, and 90 and ventilator-free days to day 28.
The six most important classifier variables were interleukin (IL)-8, IL-6, protein C, soluble tumour necrosis factor receptor 1, bicarbonate, and vasopressor use. From the nested models, three-variable (IL-8, bicarbonate, and protein C) and four-variable (3-variable plus vasopressor use) models were adjudicated to be the best performing. In the validation test set, both models showed good accuracy (AUC 0·94 95% CI 0·92-0·95 for the three-variable model and 0·95 95% CI 0·93-0·96 for the four-variable model) against LCA classifications. As with LCA-derived phenotypes, the hyperinflammatory phenotype as identified by the classifier model was associated with higher mortality at day 90 (87 39% of 223 patients vs 112 23% of 492 patients; p<0·0001) and fewer ventilator-free days (median 14 days IQR 0-22 vs 22 days 0-25; p<0·0001). In the external validation datasets, three-variable models developed in the derivation dataset identified two phenotypes with distinct clinical features and outcomes consistent with previous findings, including differential survival with simvastatin versus placebo in HARP-2 (p=0·023 for survival at 28 days).
ARDS phenotypes can be accurately identified with parsimonious classifier models using three or four variables. Pending the development of real-time testing for key biomarkers and prospective validation, these models could facilitate identification of ARDS phenotypes to enable their application in clinical trials and practice.
National Institutes of Health.
Background: Due to the clinical challenges of treatment-resistant depression (TRD), we evaluated the efficacy of mindfulness-based cognitive therapy (MBCT) relative to a structurally equivalent ...active comparison condition as adjuncts to treatment-as-usual (TAU) pharmacotherapy in TRD. Methods: This single-site, randomized controlled trial compared 8-week courses of MBCT and the Health Enhancement Program (HEP), comprising physical fitness, music therapy and nutritional education, as adjuncts to TAU pharmacotherapy for outpatient adults with TRD. The primary outcome was change in depression severity, measured by percent reduction in the total score on the 17-item Hamilton Depression Rating Scale (HAM-D17), with secondary depression indicators of treatment response and remission. Results: We enrolled 173 adults; mean length of a current depressive episode was 6.8 years (SD = 8.9). At the end of 8 weeks of treatment, a multivariate analysis showed that relative to the HEP condition, the MBCT condition was associated with a significantly greater mean percent reduction in the HAM-D17 (36.6 vs. 25.3%; p = 0.01) and a significantly higher rate of treatment responders (30.3 vs. 15.3%; p = 0.03). Although numerically superior for MBCT than for HEP, the rates of remission did not significantly differ between treatments (22.4 vs. 13.9%; p = 0.15). In these models, state anxiety, perceived stress and the presence of personality disorder had adverse effects on outcomes. Conclusions: MBCT significantly decreased depression severity and improved treatment response rates at 8 weeks but not remission rates. MBCT appears to be a viable adjunct in the management of TRD.
OBJECTIVE: The Patient Health Questionnaire depression scale (PHQ‐9) is a well‐validated, Diagnostic and Statistical Manual of Mental Disorders— Fourth Edition (DSM‐IV) criterion‐based measure for ...diagnosing depression, assessing severity and monitoring treatment response. The performance of most depression scales including the PHQ‐9, however, has not been rigorously evaluated in different racial/ethnic populations. Therefore, we compared the factor structure of the PHQ‐9 between different racial/ethnic groups as well as the rates of endorsement and differential item functioning (DIF) of the 9 items of the PHQ‐9. The presence of DIF would indicate that responses to an individual item differ significantly between groups, controlling for the level of depression.
MEASUREMENTS: A combined dataset from 2 separate studies of 5,053 primary care patients including non‐Hispanic white (n=2,520), African American (n=598), Chinese American (n=941), and Latino (n=974) patients was used for our analysis. Exploratory principal components factor analysis was used to derive the factor structure of the PHQ‐9 in each of the 4 racial/ethnic groups. A generalized Mantel‐Haenszel statistic was used to test for DIF.
RESULTS: One main factor that included all PHQ‐9 items was found in each racial/ethnic group with α coefficients ranging from 0.79 to 0.89. Although endorsement rates of individual items were generally similar among the 4 groups, evidence of DIF was found for some items.
CONCLUSIONS: Our analyses indicate that in African American, Chinese American, Latino, and non‐Hispanic white patient groups the PHQ‐9 measures a common concept of depression and can be effective for the detection and monitoring of depression in these diverse populations.
In acute respiratory distress syndrome (ARDS) unrelated to COVID-19, two phenotypes, based on the severity of systemic inflammation (hyperinflammatory and hypoinflammatory), have been described. The ...hyperinflammatory phenotype is known to be associated with increased multiorgan failure and mortality. In this study, we aimed to identify these phenotypes in COVID-19-related ARDS.
In this prospective observational study done at two UK intensive care units, we recruited patients with ARDS due to COVID-19. Demographic, clinical, and laboratory data were collected at baseline. Plasma samples were analysed for interleukin-6 (IL-6) and soluble tumour necrosis factor receptor superfamily member 1A (TNFR1) using a novel point-of-care assay. A parsimonious regression classifier model was used to calculate the probability for the hyperinflammatory phenotype in COVID-19 using IL-6, soluble TNFR1, and bicarbonate levels. Data from this cohort was compared with patients with ARDS due to causes other than COVID-19 recruited to a previous UK multicentre, randomised controlled trial of simvastatin (HARP-2).
Between March 17 and April 25, 2020, 39 patients were recruited to the study. Median ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO
/FiO
) was 18 kpa (IQR 15-21) and acute physiology and chronic health evaluation II score was 12 (10-16). 17 (44%) of 39 patients had died by day 28 of the study. Compared with survivors, patients who died were older and had lower PaO
/FiO
. The median probability for the hyperinflammatory phenotype was 0·03 (IQR 0·01-0·2). Depending on the probability cutoff used to assign class, the prevalence of the hyperinflammatory phenotype was between four (10%) and eight (21%) of 39, which is lower than the proportion of patients with the hyperinflammatory phenotype in HARP-2 (186 35% of 539). Using the Youden index cutoff (0·274) to classify phenotype, five (63%) of eight patients with the hyperinflammatory phenotype and 12 (39%) of 31 with the hypoinflammatory phenotype died. Compared with matched patients recruited to HARP-2, levels of IL-6 were similar in our cohort, whereas soluble TNFR1 was significantly lower in patients with COVID-19-associated ARDS.
In this exploratory analysis of 39 patients, ARDS due to COVID-19 was not associated with higher systemic inflammation and was associated with a lower prevalence of the hyperinflammatory phenotype than that observed in historical ARDS data. This finding suggests that the excess mortality observed in COVID-19-related ARDS is unlikely to be due to the upregulation of inflammatory pathways described by the parsimonious model.
US National Institutes of Health, Innovate UK, and Randox.
Treatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for ...administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS.
We did a prospective, double-blind, multicentre, randomised trial to assess treatment with one intravenous dose of MSCs compared with placebo. We recruited ventilated patients with moderate to severe ARDS (ratio of partial pressure of oxygen to fractional inspired oxygen <27 kPa and positive end-expiratory pressure PEEP ≥8 cm H
O) in five university medical centres in the USA. Patients were randomly assigned 2:1 to receive either 10 × 10
/kg predicted bodyweight MSCs or placebo, according to a computer-generated schedule with a variable block design and stratified by site. We excluded patients younger than 18 years, those with trauma or moderate to severe liver disease, and those who had received cancer treatment in the previous 2 years. The primary endpoint was safety and all analyses were done by intention to treat. We also measured biomarkers in plasma. MSC viability was tested in a post-hoc analysis. This trial is registered with ClinicalTrials.gov, number NCT02097641.
From March 24, 2014, to Feb 9, 2017 we screened 1038 patients, of whom 60 were eligible for and received treatment. No patient experienced any of the predefined MSC-related haemodynamic or respiratory adverse events. One patient in the MSC group died within 24 h of MSC infusion, but death was judged to be probably unrelated. 28-day mortality did not differ between the groups (30% in the MSC group vs 15% in the placebo group, odds ratio 2·4, 95% CI 0·5-15·1). At baseline, the MSC group had numerically higher mean scores than the placebo group for Acute Physiology and Chronic Health Evaluation III (APACHE III; 104 SD 31 vs 89 33), minute ventilation (11·1 3·2 vs 9·6 2·4 L/min), and PEEP (12·4 3·7 vs 10·8 2·6 cm H
O). After adjustment for APACHE III score, the hazard ratio for mortality at 28 days was 1·43 (95% CI 0·40-5·12, p=0·58). Viability of MSCs ranged from 36% to 85%.
One dose of intravenous MSCs was safe in patients with moderate to severe ARDS. Larger trials are needed to assess efficacy, and the viability of MSCs must be improved.
National Heart, Lung, and Blood Institute.
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