Moyennage de modèles pour l'estimation d'effets causaux avec la méthode de pondération par les probabilités inversées

Pour estimer un effet causal dans les études d'observation en épidémiologie, les méthodes de pondération par les probabilités inversées et les méthodes doublement robustes sont couramment utilisées. Il n'est toutefois pas facile de spécifier correctement le modèle de traitement et les estimateurs associés sont particulièrement sensibles à un choix de modèle incorrect. Le but principal de ce projet est de déterminer si le fait de prendre une moyenne sur plusieurs modèles pourrait améliorer la performance des estimateurs par pondération par les probabilités inversées, en comparaison à une estimation basée sur un seul modèle. Pour ce faire, nous utilisons les critères d'ajustement AIC et BIC pour associer un poids (probabilité) à chacun des modèles. Nous nous intéressons plus particulièrement à deux façons d'utiliser ces poids 1) soit la pondération externe qui considère une moyenne des estimations obtenues sous chacun des modèles de l'ensemble des modèles considérés, et 2) la pondération interne qui effectue une moyenne des scores de propension obtenus sous chacun des modèles pour ensuite obtenir l'estimation correspondante. Nous comparons les résultats obtenus sons chacun des modèles individuellement, puis sous les différentes façons proposées de considérer un ensemble de modèles. Nous regardons la performance des techniques lorsque le vrai modèle fait ou ne fait pas partie des modèles considérés. Nous obtenons que la pondération apporte un compromis intéressant pour pallier l'incertitude reliée à la sélection du modèle de traitement. Nous observons que l'estimateur basé sur la pondération interne semble avoir une variance plus petite que l'estimateur basé sur la pondération externe et que l'estimateur par pondération par les probabilités inversées employé sur les modèles individuellement, surtout lorsqu'ils sont appliqués sur des échantillons de petite taille. \ud ______________________________________________________________________________ \ud MOTS-CLÉS DE L’AUTEUR : estimation causale, sélection de modèle, moyennage de modèles, étude d'observation, pondération par probabilités inversées

Beneficial effects of reconstituted high-density lipoprotein (rHDL) on circulating CD34+ cells in patients after an acute coronary syndrome

Background: High-density lipoproteins (HDL) favorably affect endothelial progenitor cells (EPC). Circulating progenitor cell level and function are impaired in patients with acute coronary syndrome (ACS). This study investigates the short-term effects of reconstituted HDL (rHDL) on circulating progenitor cells in patients with ACS. Methods and Findings: The study population consisted of 33 patients with recent ACS: 20 patients from the ERASE trial (randomized to receive 4 weekly intravenous infusions of CSL-111 40 mg/kg or placebo) and 13 additional patients recruited as controls using the same enrolment criteria. Blood was collected from 16 rHDL (CSL-111)-treated patients and 17 controls at baseline and at 6–7 weeks (i.e. 2–3 weeks after the fourth infusion of CSL-111 in ERASE). CD34+ and CD34+/kinase insert domain receptor (KDR+) progenitor cell counts were analyzed by flow cytometry. We found preserved CD34+ cell counts in CSL-111-treated subjects at follow-up (change of 1.6%), while the number of CD34+ cells was reduced (-32.9%) in controls (p = 0.017 between groups). The level of circulating SDF-1 (stromal cell-derived factor-1), a chemokine involved in progenitor cell recruitment, increased significantly (change of 21.5%) in controls, while it remained unchanged in CSL-111-treated patients (p = 0.031 between groups). In vitro exposure to CSL-111 of early EPC isolated from healthy volunteers significantly increased CD34+ cells, reduced early EPC apoptosis and enhanced their migration capacity towards SDF-1. Conclusions: The relative increase in circulating CD34+ cells and the low SDF-1 levels observed following rHDL infusions in ACS patients point towards a role of rHDL in cardiovascular repair mechanisms

The Benefits Conferred by Radial Access for Cardiac Catheterization Are Offset by a Paradoxical Increase in the Rate of Vascular Access Site Complications With Femoral Access The Campeau Radial Paradox

AbstractObjectivesThe purpose of this study was to assess whether the benefits conferred by radial access (RA) at an individual level are offset by a proportionally greater incidence of vascular access site complications (VASC) at a population level when femoral access (FA) is performed.BackgroundThe recent widespread adoption of RA for cardiac catheterization has been associated with increased rates of VASCs when FA is attempted.MethodsLogistic regression was used to calculate the adjusted VASC rate in a contemporary cohort of consecutive patients (2006 to 2008) where both RA and FA were used, and compared it with the adjusted VASC rate observed in a historical control cohort (1996 to 1998) where only FA was used. We calculated the adjusted attributable risk to estimate the proportion of VASC attributable to the introduction of RA in FA patients of the contemporary cohort.ResultsA total of 17,059 patients were included. At a population level, the VASC rate was higher in the overall contemporary cohort compared with the historical cohort (adjusted rates: 2.91% vs. 1.98%; odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.17 to 1.89; p = 0.001). In the contemporary cohort, RA patients experienced fewer VASC than FA patients (adjusted rates: 1.44% vs. 4.19%; OR: 0.33, 95% CI: 0.23 to 0.48; p < 0.001). We observed a higher VASC rate in FA patients in the contemporary cohort compared with the historical cohort (adjusted rates: 4.19% vs. 1.98%; OR: 2.16, 95% CI: 1.67 to 2.81; p < 0.001). This finding was consistent for both diagnostic and therapeutic catheterizations separately. The proportion of VASCs attributable to RA in the contemporary FA patients was estimated at 52.7%.ConclusionsIn a contemporary population where both RA and FA were used, the safety benefit associated with RA is offset by a paradoxical increase in VASCs among FA patients. The existence of this radial paradox should be taken into consideration, especially among trainees and default radial operators

Brain-derived neurotrophic factor mitigates the association between platelet dysfunction and cognitive impairment

Background: Platelet hyperactivity is deleterious in coronary artery disease (CAD), requiring lifelong antiplatelet therapy, and is associated with worse cognitive outcomes. Upon activation, platelets release Brain-Derived Neurotrophic Factor (BDNF), a neurotrophin protective against cognitive decline. Given these apparently opposing effects of platelet activation on cognitive health, we investigated whether BDNF levels intercede in the relationship between platelet activation and cognitive function; and whether this relationship is moderated by the presence of CAD. Methods: In this cross-sectional study, 1,280 participants with (n = 673) and without CAD (n = 607) completed the Montreal Cognitive Assessment (MoCA). Plasma BDNF and soluble P-selectin (a marker of platelet activity) levels were assessed using multiplex flow cytometry. Results: In a mediation model, platelet activity was correlated with higher plasma BDNF concentrations (b = 0.53, p < 0.0001). The relationship between sP-selectin and BDNF concentrations was stronger for individuals without CAD (b = 0.71, p < 0.0001) than for CAD participants (b = 0.43, p < 0.0001; pinteraction < 0.0001). Higher BDNF concentrations were associated with higher MoCA scores (b = 0.26, p = 0.03). The overall effect of platelet activity on cognitive performance was non-significant (total effect: b = −0.12, p = 0.13), and became significant when accounting for BDNF as a mediating factor (direct effect: b = −0.26, p = 0.01). This resulted in a positive indirect effect of platelet activity (via BDNF) on MoCA scores (b = 0.14, CI 95% 0.02–0.30), that was smaller in CAD participants than in non-CAD participants [1 −0.07 (95% CI −0.14 to −0.01)]. Conclusions: BDNF released from activated platelets could be a mitigating factor in a negative association between platelet activity and cognitive function

Changes in Cardiopulmonary Reserve and Peripheral Arterial Function Concomitantly with Subclinical Inflammation and Oxidative Stress in Patients with Heart Failure with Preserved Ejection Fraction

Background. Changes in cardiopulmonary reserve and biomarkers related to wall stress, inflammation, and oxidative stress concomitantly with the evaluation of peripheral arterial blood flow have not been investigated in patients with heart failure with preserved ejection fraction (HFpEF) compared with healthy subjects (CTL). Methods and Results. Eighteen HFpEF patients and 14 CTL were recruited. Plasma levels of inflammatory and oxidative stress biomarkers were measured at rest. Brain natriuretic peptide (BNP) was measured at rest and peak exercise. Cardiopulmonary reserve was assessed using an exercise protocol with gas exchange analyses. Peripheral arterial blood flow was determined by strain gauge plethysmography. Peak VO2 (12.0±0.4 versus 19.1±1.1 mL/min/kg, P<0.001) and oxygen uptake efficiency slope (1.55±0.12 versus 2.06±0.14, P<0.05) were significantly decreased in HFpEF patients compared with CTL. BNP at rest and following stress, C-reactive-protein, interleukin-6, and TBARS were significantly elevated in HFpEF. Both basal and posthyperemic arterial blood flow were not significantly different between the HFpEF patients and CTL. Conclusions. HFpEF exhibits a severe reduction in cardiopulmonary reserve and oxygen uptake efficiency concomitantly with an elevation in a broad spectrum of biomarkers confirming an inflammatory and prooxidative status in patients with HFpEF

<i>In vitro</i> exposure of circulating progenitor cells to CSL-111.

<p>Peripheral blood mononuclear cells (PBMCs) were isolated from healthy donors (n = 7) and plated on fibronectin-coated plates in the absence or presence of CSL-111 (1 mg/mL) from day 0 to day 4 (D0-4), 4 to 7 (D4-7) or 0 to 7 (D0-7). After 7 days of culture, adherent cells were harvested and analyzed by flow cytometry. (A) All adherent cells were quantified by flow cytometry using cell counting beads for enumeration. (B) CSL-111 treatment increases the total number of CD34⁺ cells when added to cell culture media at D0-4 and D0-7; CD34⁺ cells were quantified by flow cytometry. (C) CSL-111 treatment reduces basal apoptosis in eEPCs when added to cell culture media at D0-4 and D0-7. Apoptosis was measured by flow cytometry using Annexin V labeling. Each box plot shows the median, the interquartile range, the maximum and the minimum of the relative change. * indicates p < 0.05 between groups from Wilcoxon signed-rank tests.</p

Representative example of sequential gating strategy for flow cytometric analysis of endothelial progenitor cells.

<p>A modified ISHAGE strategy was applied for EPC quantification. 1) Representative sample stained with CD45-FITC. Region R6 represents lymphocytes. 2) Anti-CD34-PE staining of cells from R1. Region R2 represents CD34⁺ cells. 3) Region R3 is placed to include the low Side Scatter and low to intermediate CD45 staining. 4) R4 represents all events from regions R1, R2 and R3 displayed on a FSC vs SSC dot plot to confirm that the selected events fall into a lymph-blast region. 5) Displays the events included in regions R1, R2, R3 and R4. A quadrant was positioned to separate the positive and the negative cells for VEGFR2 staining. An appropriate isotype control was used to adequately place the quadrant. Region R5 represents the total EPCs (CD34+/VEGFR2+ cells). 6) Events from region R6. This region is used to set the region R4. 7) All events. This histogram is useful to establish the lower limit of CD45 expression for the CD34⁺ events. The region R8 is placed in the right top of the histogram to count all Stem-count fluorospheres accumulated for each sample for absolute quantification. 8) Events from region R8. This region includes the Stem-count fluorospheres singlet population.</p

Decreased levels of serum stromal cell-derived factor-1 (SDF-1) in patients with acute coronary syndrome following treatment with reconstituted high-density lipoprotein (rHDL) compared to controls.

<p>Relative changes from baseline in serum SDF-1 in the control group and in the rHDL-treated group. Each box plot shows the median, the interquartile range, the maximum and the minimum. p < 0.05 between groups from Mann-Whitney test.</p