Improving the decision to switch from first- to second-line therapy in multiple sclerosis: A dynamic scoring system.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), early identification of suboptimal responders can prevent disability progression. OBJECTIVE: We aimed to develop and validate a dynamic score to guide the early decision to switch from first- to second-line therapy. METHODS: Using time-dependent propensity scores (PS) from a French cohort of 12,823 patients with RRMS, we constructed one training and two validation PS-matched cohorts to compare the switched patients to second-line treatment and the maintained patients. We used a frailty Cox model for predicting individual hazard ratios (iHRs). RESULTS: From the validation PS-matched cohort of 348 independent patients with iHR ⩽ 0.69, we reported the 5-year relapse-free survival at 0.14 (95% confidence interval (CI) 0.09-0.22) for the waiting group and 0.40 (95% CI 0.32-0.51) for the switched group. From the validation PS-matched cohort of 518 independent patients with iHR > 0.69, these values were 0.37 (95% CI 0.30-0.46) and 0.44 (95% CI 0.37-0.52), respectively. CONCLUSIONS: By using the proposed dynamic score, we estimated that at least one-third of patients could benefit from an earlier switch to prevent relapse.

Association Between Deceased Donor Acute Kidney Injury Assessed Using Baseline Serum Creatinine Back-Estimation and Graft Survival: Results From the French National CRISTAL Registry.

RATIONALE & OBJECTIVE: Deceased donor acute kidney injury (AKI) frequently leads to kidney discards, but its impact on long-term graft survival in kidney transplant recipients remains unclear. We investigated the association between deceased donor AKI assessed using back-estimation of baseline serum creatinine (Scr) and graft survival. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Adult patients represented within the French CRISTAL registry who received a single kidney allograft from brain-dead deceased donors between January 2006 and December 2017. EXPOSURE: A back-estimated Scr baseline value was derived for an assumed glomerular filtration rate at 75mL/min/1.73m2, using the MDRD Study equation. A refined classification system for donor AKI was implemented as follows: no AKI, undetermined AKI/chronic kidney disease (CKD), recovery from AKI, and ongoing AKI. OUTCOME: Death-censored graft survival. ANALYTICAL APPROACH: Multivariable Cox models using a robust variance estimator for paired kidneys from the same donor. RESULTS: We classified 26,786 recipients as follows: no AKI (n=19,276); undetermined AKI/CKD (n=1,745); recovery from AKI (n=2,392); and ongoing AKI (n=3,373). We observed 4,458 kidney graft losses during a median follow-up period of 5.7 years. Compared with no AKI, ongoing AKI was associated with an increased risk of graft failure (hazard ratio [HR], 1.24 [95% CI, 1.13-1.35]). The HRs for graft failure in the undetermined AKI/CKD and recovery from AKI groups (1.22 [95% CI, 1.07-1.38] and 1.18 [95% CI, 1.06-1.31], respectively) were similar to those observed in the ongoing AKI group. The adverse effect of deceased donor AKI was no longer evident when relying either on the admission or the lowest Scr throughout the procurement procedure as baseline Scr. LIMITATIONS: No measurement of urine output in donors. CONCLUSIONS: Deceased donor ongoing AKI, undetermined AKI/CKD, and recovery from AKI according to back-estimated baseline Scr are associated with decreased graft survival. The definition of baseline Scr as the first value measured on admission would have led to a misclassification bias and erroneous estimates.

Impact of kidney transplantation in obese candidates: a time-dependent propensity score matching study.

BACKGROUND: Although kidney transplantation (KT) is considered the best treatment for end-stage renal disease (ESRD), there are concerns about its benefit in the obese population because of the increased incidence of post-transplant adverse events. We compared patients who underwent KT versus patients awaiting KT on dialysis. METHODS: We estimated the life expectancy [restricted mean survival time (RMST)] for a 10-year follow-up by matching on time-dependent propensity scores. The primary outcome was time to death. RESULTS: In patients with a body mass index (BMI) ≥30 kg/m2 (n = 2155 patients per arm), the RMST was 8.23 years [95% confidence interval (CI) 8.05-8.40] in the KT group versus 8.00 years (95% CI 7.82-8.18) in the awaiting KT group, a difference of 2.71 months (95% CI -0.19-5.63). In patients with a BMI ≥35 kg/m2 (n = 212 patients per arm), we reported no significant difference [8.56 years (95% CI 7.96-9.08) versus 8.66 (95% CI 8.10-9.17)]. Hence we deduced that KT in patients with a BMI between 30 and 35 kg/m2 was beneficial in terms of life expectancy. CONCLUSION: Regarding the organ shortage, KT may be questionable for those with a BMI ≥35 kg/m2. These results do not mean that a BMI ≥35 kg/m2 should be a barrier to KT, but it should be accounted for in allocation systems to better assign grafts and maximize the overall life expectancy of ESRD patients.

Causal inference in case of near-violation of positivity: comparison of methods.

In causal studies, the near-violation of the positivity may occur by chance, because of sample-to-sample fluctuation despite the theoretical veracity of the positivity assumption in the population. It may mostly happen when the exposure prevalence is low or when the sample size is small. We aimed to compare the robustness of g-computation (GC), inverse probability weighting (IPW), truncated IPW, targeted maximum likelihood estimation (TMLE), and truncated TMLE in this situation, using simulations and one real application. We also tested different extrapolation situations for the sub-group with a positivity violation. The results illustrated that the near-violation of the positivity impacted all methods. We demonstrated the robustness of GC and TMLE-based methods. Truncation helped in limiting the bias in near-violation situations, but at the cost of bias in normal conditions. The application illustrated the variability of the results between the methods and the importance of choosing the most appropriate one. In conclusion, compared to propensity score-based methods, methods based on outcome regression should be preferred when suspecting near-violation of the positivity assumption.

Time-dependent lymphocyte count after transplantation is associated with higher risk of graft failure and death.

The transplantation field requires the identification of specific risk factors associated with the level of immunosuppression. Here, our aim was to analyze the association between the number of circulating lymphocytes, monitored routinely by complete blood cell counts during outpatient visits, and patient and graft survival. In total, 2,999 kidney or combined kidney-pancreas recipients transplanted between 2000 and 2016, from two University hospitals, were enrolled. We investigated the etiological relationship between time-dependent lymphocyte count beyond one year after transplantation and patient and graft survival, viral infection and cancer risk using time-dependent multivariate Cox models. Model 1 considered kidney function at one year and model 2 as time-dependent variable. At the time of inclusion (one year after transplantation), 584 patients (19.4%) had deep lymphopenia (under 750 /mm3) and 1,072 (35.7%) had a normal count (over 1,500 /mm3). A patient with deep lymphopenia at a given follow-up time had significantly higher risks of graft failure, death and viral infection than comparable patients with a normal lymphocyte count at the same time point. Thus, after the first year of transplantation, the occurrence of deep lymphopenia within a patient's follow-up is a risk factor for long-term graft failure, death and viral infection.

Clinical Trial Emulation by Matching Time-dependent Propensity Scores: The Example of Estimating Impact of Kidney Transplantation.

BACKGROUND: No study to our knowledge has examined the use of observational data to emulate a clinical trial whereby patients at the time of kidney transplant proposal are randomly assigned to an awaiting transplantation or transplantation group. The main methodologic issue is definition of the baseline for dialyzed patients assigned to awaiting transplantation, resulting in the inability to use common propensity score-based approaches. We aimed to use time-dependent propensity score to better appraise the benefit of transplantation. METHODS: We studied 23,231 patients included in the French registry and on a transplant waiting list from 2005 to 2016. The main outcome was time to death. By matching on time-dependent propensity score, we obtained 10,646 pairs of recipients (transplantation group) versus comparable patients remaining on dialysis (awaiting transplantation group). RESULTS: The baseline exposure, that is, pseudo-randomization, was matching time. Median follow-up time was 3.5 years. At 10 years' follow-up, the restricted mean survival time was 8.8 years [95% confidence interval (CI) = 8.7, 8.9] in the transplantation group versus 8.2 years (95% CI = 8.1, 8.3) in the awaiting transplantation group. The corresponding life expectancy gain was 6.8 months (95% CI = 5.5, 8.2), and this corresponded to one prevented death at 10 years for 13 transplantations. CONCLUSIONS: Our study has estimated the life expectancy gain due to kidney transplantation. It confirms transplantation as the best treatment for end-stage renal disease. Furthermore, we demonstrated that this simple method should also be considered for estimating marginal effects of time-dependent exposures.

Terminally Differentiated Effector Memory CD8+ T Cells Identify Kidney Transplant Recipients at High Risk of Graft Failure.

BACKGROUND: Identifying biomarkers to predict kidney transplant failure and to define new therapeutic targets requires more comprehensive understanding of the immune response to chronic allogeneic stimulation. METHODS: We investigated the frequency and function of CD8+ T cell subsets-including effector memory (EM) and terminally differentiated EM (TEMRA) CD8+ T cells-in blood samples from 284 kidney transplant recipients recruited 1 year post-transplant and followed for a median of 8.3 years. We also analyzed CD8+ T cell reactivity to donor-specific PBMCs in 24 patients who had received living-donor kidney transplants. RESULTS: Increased frequency of circulating TEMRA CD8+ T cells at 1 year post-transplant associated with increased risk of graft failure during follow-up. This association remained after adjustment for a previously reported composite of eight clinical variables, the Kidney Transplant Failure Score. In contrast, increased frequency of EM CD8+ T cells associated with reduced risk of graft failure. A distinct TEMRA CD8+ T cell subpopulation was identified that was characterized by expression of FcγRIIIA (CD16) and by high levels of proinflammatory cytokine secretion and cytotoxic activity. Although donor-specific stimulation induced a similar rapid, early response in EM and TEMRA CD8+ T cells, CD16 engagement resulted in selective activation of TEMRA CD8+ T cells, which mediated antibody-dependent cytotoxicity. CONCLUSIONS: At 1 year post-transplant, the composition of memory CD8+ T cell subsets in blood improved prediction of 8-year kidney transplant failure compared with a clinical-variables score alone. A subpopulation of TEMRA CD8+ T cells displays a novel dual mechanism of activation mediated by engagement of the T-cell receptor or of CD16. These findings suggest that TEMRA CD8+ T cells play a pivotal role in humoral and cellular rejection and reveal the potential value of memory CD8+ T cell monitoring for predicting risk of kidney transplant failure.

Comparison of machine perfusion versus cold storage in kidney transplant recipients from expanded criteria donors: a cohort-based study.

BACKGROUND: Most studies comparing the efficacy of hypothermic machine perfusion (HMP) versus static cold storage (SCS) are based on short-term outcomes. We aimed to better evaluate the mid-term impact of HMP in patients receiving expanded criteria donor (ECD) kidneys. METHODS: The analyses were based on the French Données Informatisées et VAlidées en Transplantation (DIVAT) observational cohort. Patients aged ≥45 years transplanted for the first or second times from an ECD donor since 2010 were studied. Our study reported the graft and/or patient survivals and the incidence of acute rejection episode. The Cox models and the Kaplan-Meier estimators, weighted on the propensity score, were used to study the times-to-events. RESULTS: Among the 2019 included patients, 1073 were in the SCS group versus 946 in the HMP group. The mean life expectancy with functioning graft was 5.7 years [95% confidence interval (CI) 5.4-6.1] for the HMP cohort followed-up for 8 years post-transplantation versus 6.0 years (95% CI 5.7-6.2) for the SCS group. These mid-term results were comparable in the patients receiving grafts from donors aged ≥70 years and in the transplantations with cold ischaemia time ≥18 h. CONCLUSIONS: Our study challenges the utility of using HMP to improve mid-term patient and graft survival. Nevertheless, the improvement of the short-term outcomes is indisputable. It is necessary to continue technological innovations to obtain long-term results.

The weekend effect in kidney transplantation outcomes: a French cohort-based study.

Numerous studies have reported a weekend effect on outcomes for diseases treated at hospitals. No study has been conducted in France for kidney transplantation. We therefore performed a cohort-based study to evaluate whether outcomes of kidney transplant recipients display a weekend effect. Data were extracted from the French DIVAT cohort. Patients aged 18 years and older, transplanted with a single kidney from deceased donors between 2005 and 2017 were studied. Linear regression, logistic regression, and cause-specific Cox model were used. Among the 6652 studied patients, 4653 patients were transplanted during weekdays (69.9%) versus 1999 during weekends (30.1%). The only statistically significant difference was the percentage of patients with vascular surgical complication(s) at 30 days: 13.3% in the weekend group versus 16.2% in the weekday group 0.79 (95% CI: 0.68; 0.92). We did not observe other significant differences for the other outcomes: patient or graft survival, the risk of acute rejection episodes, the 30-day percentage of urological complications, and the 1-year estimated glomerular filtration rate. Our study highlights a small protective weekend effect with less post-surgery vascular complications compared to weekdays. This paradox might be explained by a different handling of weekend transplantations.

Long-term effect of first-line injectable multiple sclerosis treatments: Input of a time-dependent propensity score.

PURPOSE: The long-term effect of beta-interferon and glatiramer acetate on multiple sclerosis (MS) disability progression has resulted in controversial results, probably due to a lack of appropriate control of biases as raised in observational studies. In particular, the time of the therapeutic decision is difficult to define when the controls are not treated. METHODS: This retrospective observational study was based on a series of patients from the MS expert center in Rennes, France. We used a time-dependent propensity score defined as the linear predictor of a Cox model estimating the hazard of being treated at each time from MS onset. The matching procedure resulted in two groups: patients matched as treated and as not yet treated. The restricted mean times (RMST) to reach a moderate level of disability or worsening of the disability were compared between the two groups in an intention-to-treat analysis. RESULTS: Of the 2383 patients included in the study, 556 were matched as treated. The matching procedure provided a good balance of both the time-fixed and the time-dependent covariates. A slight difference was observed for the time to reach a moderate level of disability, in favor of the "not yet treated" group (difference in the RMST: -0.62 [-0.91; -0.33]) while no difference was found in terms of worsening of the disability (-0.03 [-0.24; 0.33]). CONCLUSION: This unexpected result is probably due to unmeasured confounders. However, this time-dependent PS warrants consideration in long-term effectiveness studies.

Patient-centered simulations to assess the usefulness of the 70-gene signature for adjuvant chemotherapy administration in early-stage breast cancer.

PURPOSE: From the MINDACT trial, Cardoso et al. did not demonstrate a significant efficacy for adjuvant chemotherapy (CT) for women with early-stage breast cancer presenting high clinical and low genomic risks. Our objective was to assess the usefulness of the 70-gene signature in this population by using an alternative endpoint: the number of Quality-Adjusted Life-Years (QALYs), i.e., a synthetic measure of quantity and quality of life. METHODS: Based on the results of the MINDACT trial, we simulated a randomized clinical trial consisting of 1497 women with early-stage breast cancer presenting high clinical and low genomic risks. The individual preferences for the different health states and corresponding decrements were obtained from the literature. RESULTS: The gain in terms of 5-year disease-free survival was 2.8% (95% CI from - 0.1 to 5.7%, from 90.4% for women without CT to 93.3% for women with CT). In contrast, due to the associated side effects, CT significantly reduced the number of QALYs by 62 days (95% CI from 55 to 70 days, from 4.13 years for women without CT to 3.96 years for women with CT). CONCLUSION: Our results support the conclusions published by Cardoso et al. by providing additional evidence that the 70-gene signature can be used to avoid overtreatment by CT for women with high clinical risk but low genomic risk.

Lack of impact of pre-emptive deceased-donor kidney transplantation on graft outcomes: a propensity score-based study.

BACKGROUND: A significant number of studies have compared graft outcomes between patients with Pre-emptive Kidney Transplantation (PreKT) and patients on Dialysis before their Kidney Transplantation (DiaKT). These studies have suffered from the limitation that the DiaKT group is composed of all the dialysed patients, including those placed on a waiting list at the time of their first dialysis session. This seriously questions the comparability of these patients with those placed on the waiting list a long time before the need for renal replacement therapy. The aim of this study was to precisely evaluate the causal effect of PreKT from deceased donors. METHODS: Data were extracted from the multicentric French DIVAT (Données Informatisées et VAlidées en Transplantation) cohort. The DiaKT group was composed of patients placed on the waiting list with an initial intention of pre-emptive transplantation. Cause-specific Cox models with propensity scores (inverse probability weighting) were used to study the patient and graft outcomes. RESULTS: Among the 1138 included patients, 554 patients were in the PreKT group. The outcomes of the PreKT group were similar compared with the DiaKT group. In particular, the life expectancy with a functioning graft was 8.51 years [95% confidence interval (CI) 8.20-8.81] for the PreKT recipients versus 8.49 years (95% CI 8.15-8.84) for the DiaKT recipients. CONCLUSIONS: Our results challenge the utility of PreKTs from deceased donors, especially with regard to the consequential increase in the waiting list.

Dynamic predictions of long-term kidney graft failure: an information tool promoting patient-centred care.

BACKGROUND: Informing kidney transplant recipients of their prognosis and disease progression is of primary importance in a patient-centred vision of care. By participating in decisions from the outset, transplant recipients may be more adherent to complex medical regimens due to their enhanced understanding. METHODS: We proposed to include repeated measurements of serum creatinine (SCr), in addition to baseline characteristics, in order to obtain dynamic predictions of the graft failure risk that could be updated continuously during patient follow-up. Adult recipients from the French Données Informatisées et VAlidées en Transplantation (DIVAT) cohort transplanted for the first or second time from a heart-beating or living donor and alive with a functioning graft at 1 year post-transplantation were included. RESULTS: The model was composed of six baseline parameters, in addition to the SCr evolution. We validated the dynamic predictions by evaluating both discrimination and calibration accuracy. The area under the receiver operating characteristic curve varied from 0.72 to 0.76 for prediction times at 1 and 6 years post-transplantation, respectively, while calibration plots showed correct accuracy. We also provided an online application tool (https://shiny.idbc.fr/DynPG). CONCLUSION: We have created a tool that, for the first time in kidney transplantation, predicts graft failure risk both at an individual patient level and dynamically. We believe that this tool would encourage willing patients into participative medicine.

Comparison of graft and patient survival according to the transplantation centre policy for 1-year screening biopsy among stable kidney recipients: a propensity score-based study.

BACKGROUND: The clinical utility of screening biopsies (SBs) at 1 year post-transplantation is still debated, especially for stable kidney graft recipients. Given the heterogeneity in practices between transplantation centres, the objective of this study was to compare graft and patient survival of stable patients according to whether they were followed up in a transplantation centre with or without a policy for having an SB at 1 year post-transplantation. MATERIALS: From a French multicentre cohort, we studied 1573 kidney recipients who were alive with stable graft function at 1 year post-transplantation, with no acute rejection in their first year post-transplantation. RESULTS: Using propensity score-based analyses, we did not observe any significant difference in the relative risk for graft failure between patients from centres with a 1-year SB policy and those from other centres [hazard ratio = 1.15, 95% confidence interval (CI) 0.86-1.53]. The corresponding adjusted survival probability at 8 years post-transplantation was 69% (95% CI 61-74%) for patients from centres with a 1-year SB policy versus 74% (95% CI 67-79%) for those from other centres. CONCLUSION: A 1-year SB policy for stable patients may not lead to therapeutical benefits for improved graft and patient survival. Further studies examining the benefits versus the risks of a 1-year SB policy are warranted to demonstrate the long-term utility of this intervention.

Meta-analysis of predictive models to assess the clinical validity and utility for patient-centered medical decision making: application to the CAncer of the Prostate Risk Assessment (CAPRA).

BACKGROUND: The Cancer of the Prostate Risk Assessment (CAPRA) score was designed and validated several times to predict the biochemical recurrence-free survival after a radical prostatectomy. Our objectives were, first, to study the clinical validity of the CAPRA score, and, second, to assess its clinical utility for stratified medicine from an original patient-centered approach. METHODS: We proposed a meta-analysis based on a literature search using MEDLINE. Observed and predicted biochemical-recurrence-free survivals were compared to assess the calibration of the CAPRA score. Discriminative capacities were evaluated by estimating the summary time-dependent ROC curve. The clinical utility of the CAPRA score was evaluated according to the following stratified decisions: active monitoring for low-risk patients, prostatectomy for intermediate-risk patients, or radio-hormonal therapy for high risk patients. For this purpose, we assessed CAPRA's clinical utility in terms of its ability to maximize time-dependent utility functions (i.e. Quality-Adjusted Life-Years - QALYs). RESULTS: We identified 683 manuscripts and finally retained 9 studies. We reported good discriminative capacities with an area under the SROCt curve at 0.73 [95%CI from 0.67 to 0.79], while graphical calibration seemed acceptable. Nevertheless, we also described that the CAPRA score was unable to discriminate between the three medical alternatives, i.e. it did not allow an increase in the number of life years in perfect health (QALYs) of patients with prostate cancer. CONCLUSIONS: We confirmed the prognostic capacities of the CAPRA score. In contrast, we were not able to demonstrate its clinical usefulness for stratified medicine from a patient-centered perspective. Our results also highlighted the confusion between clinical validity and utility. This distinction should be better considered in order to develop predictive tools useful in practice.

Ventilator-Free Day Outcomes Can Be Misleading.

INTRODUCTION: Acute respiratory distress syndrome often requires invasive mechanical ventilation, with both mortality and mechanical ventilation duration as outcomes of interest. The concept of ventilator-free days has been proposed as an outcome combining these two outcomes. Here we analyzed the construction of the ventilator-free day outcome and provided a hypothetical scenario to alert physicians that such an outcome can lead to misleading interpretations. METHODS: We proposed the isoventilator-free day curve concept and, using an analytical development, illustrated how a median ventilator-free day value can actually result from very different combinations of death rates and mechanical ventilation durations. We also used a hypothetical example to compare the Student t test, Wilcoxon rank-sum test, and Gray test (which accounts for death as a competing event with extubation) in comparing exposition to mechanical ventilation. RESULTS: A median ventilator-free day value of 10 days may mean that 10% of the patients died while survivors were ventilated during a median of 14 days or that 40% died while survivors were ventilated during a median of 5 days. Changing the time horizon affected the Student t test but not the Wilcoxon rank-sum result. The Gray test was more relevant than both the Student t test and Wilcoxon rank-sum test in identifying differences in groups showing highly different mechanical ventilation duration, despite equal median ventilator-free days. This approach was also illustrated using real data. CONCLUSIONS: Use of ventilator-free days as an outcome appears to have many drawbacks. Suitable methods of analyzing time to extubation should be preferred.

Inverse probability weighting to control confounding in an illness-death model for interval-censored data.

Multistate models with interval-censored data, such as the illness-death model, are still not used to any considerable extent in medical research regardless of the significant literature demonstrating their advantages compared to usual survival models. Possible explanations are their uncommon availability in classical statistical software or, when they are available, by the limitations related to multivariable modelling to take confounding into consideration. In this paper, we propose a strategy based on propensity scores that allows population causal effects to be estimated: the inverse probability weighting in the illness semi-Markov model with interval-censored data. Using simulated data, we validated the performances of the proposed approach. We also illustrated the usefulness of the method by an application aiming to evaluate the relationship between the inadequate size of an aortic bioprosthesis and its degeneration or/and patient death. We have updated the R package multistate to facilitate the future use of this method.

The 1-year Renal Biopsy Index: a scoring system to drive biopsy indication at 1-year post-kidney transplantation.

Surveillance biopsies after renal transplantation remain debatable. To drive the decision of such intervention, we propose a predictive score of abnormal histology at 1-year post-transplantation, named 1-year Renal Biopsy Index (1-RBI). We studied 466 kidney recipients from the DIVAT cohort alive with a functioning graft and a surveillance biopsy at 1-year post-transplantation. Patients displaying abnormal histology (49%) (borderline, acute rejection, interstitial fibrosis and tubular atrophy [IFTA] grade 2 or 3, glomerulonephritis) were compared to the normal or subnormal (IFTA grade 1) histology group. Obtained from a lasso penalized logistic regression, the 1-RBI was composed of recipient gender, serum creatinine at 3, 6, and 12 month post-transplantation and anticlass II immunization at transplantation (internal validation: AUC = 0.71, 95% CI [0.53-0.83]; external validation: AUC = 0.62, 95% CI [0.58-0.66]). While we could not determinate a threshold able to identify patients at high chance of normal or subnormal histology, we estimated and validated a discriminating threshold capable of identifying a subgroup of 15% of the patients with a risk of abnormal histology higher than 80%. The 1-RBI is computable online at www.divat.fr. The 1-RBI could be a useful tool to standardize 1-year biopsy proposal and may for instance help to indicate one in case of high risk of abnormal histology.

An early increase in endothelial protein C receptor is associated with excess mortality in pneumococcal pneumonia with septic shock in the ICU.

BACKGROUND: This study investigated changes in plasma level of soluble endothelial protein C receptor (sEPCR) in association with outcome in patients with septic shock. We explored sEPCR for early sepsis prognosis assessment and constructed a scoring system based on clinical and biological data, in order to discriminate between surviving at hospital discharge and non-surviving patients. METHODS: Clinical data and samples were extracted from the prospective "STREPTOGENE" cohort. We enrolled 278 patients, from 50 intensive care units (ICUs), with septic shock caused by pneumococcal pneumonia. Patients were divided into survivors (n = 194) and non-survivors (n = 84) based on in-hospital mortality. Soluble EPCR plasma levels were quantified at day 1 (D1) and day 2 (D2) by ELISA. The EPCR gene A3 haplotype was determined. Patients were followed up until hospital discharge. Univariate and multivariate analyses were performed. A scoring system was constructed using least absolute shrinkage and selection operator (lasso) logistic regression for selecting predictive variables. RESULTS: In-hospital mortality was 30.2% (n = 84). Plasma sEPCR level was significantly higher at D1 and D2 in non-surviving patients compared to patients surviving to hospital discharge (p = 0.0447 and 0.0047, respectively). Early increase in sEPCR at D2 was found in non-survivors while a decrease was observed in the survival group (p = 0.0268). EPCR A3 polymorphism was not associated with mortality. Baseline sEPCR level and its variation from D1 to D2 were independent predictors of in-hospital mortality. The scoring system including sEPCR predicted mortality with an AUC of 0.75. CONCLUSIONS: Our findings confirm that high plasma sEPCR and its increase at D2 are associated with poor outcome in sepsis and thus we propose sEPCR as a key player in the pathogenesis of sepsis and as a potential biomarker of sepsis outcome.

Horizontal mixture model for competing risks: a method used in waitlisted renal transplant candidates.

When a patient is registered on renal transplant waiting list, she/he expects a clear information on the likelihood of being transplanted. Nevertheless, this event is in competition with death and usual models for competing events are difficult to interpret for non-specialists. We used a horizontal mixture model. Data were extracted from two French dialysis and transplantation registries. The "Ile-de-France" region was used for external validation. The other patients were randomly divided for training and internal validation. Seven variables were associated with decreased long-term probability of transplantation: age over 40 years, comorbidities (diabetes, cardiovascular disease, malignancy), dialysis longer than 1 year before registration and blood groups O or B. We additionally demonstrated longer mean time-to-transplantation for recipients under the age of 50, overweight recipients, recipients with blood group O or B and with pre-transplantation anti-HLA class I or II immunization. Our model can be used to predict the long-term probability of transplantation and the time in dialysis among transplanted patients, two easily interpretable parts. Discriminative capacities were validated on both the internal and external (AUC at 5 years = 0.72, 95% CI from 0.68 to 0.76) validation samples. However, calibration issues were highlighted and illustrated the importance of complete re-estimation of the model for other countries. We illustrated the ease of interpretation of horizontal modelling, which constitutes an alternative to sub-hazard or cause-specific approaches. Nevertheless, it would be useful to test this in practice, for instance by questioning both the physicians and the patients. We believe that this model should also be used in other chronic diseases, for both etiologic and prognostic studies.