Confidence bands for multiplicative hazards models:Flexible resampling approaches

We propose new resampling-based approaches to construct asymptotically valid time-simultaneous confidence bands for cumulative hazard functions in multistate Cox models. In particular, we exemplify the methodology in detail for the simple Cox model with time-dependent covariates, where the data may be subject to independent right-censoring or left-truncation. We use simulations to investigate their finite sample behavior. Finally, the methods are utilized to analyze two empirical examples with survival and competing risks data

Does global warming favour the occurrence of extreme floods in European Alps? First evidences from a NW Alps proglacial lake sediment record

Flood hazard is expected to increase in the context of global warming. However, long time-series of climate and gauge data at high-elevation are too sparse to assess reliably the rate of recurrence of such events in mountain areas. Here paleolimnological techniques were used to assess the evolution of frequency and magnitude of flash flood events in the North-western European Alps since the Little Ice Age (LIA). The aim was to document a possible effect of the post-19(th) century global warming on torrential floods frequency and magnitude. Altogether 56 flood deposits were detected from grain size and geochemical measurements performed on gravity cores taken in the proglacial Lake Blanc (2170 m a.s.l., Belledonne Massif, NW French Alps). The age model relies on radiometric dating (Cs-137 and Am-241), historic lead contamination and the correlation of major flood- and earthquake-triggered deposits, with recognized occurrences in historical written archives. The resulting flood calendar spans the last ca 270 years (AD 1740-AD 2007). The magnitude of flood events was inferred from the accumulated sediment mass per flood event and compared with reconstructed or homogenized datasets of precipitation, temperature and glacier variations. Whereas the decennial flood frequency seems to be independent of seasonal precipitation, a relationship with summer temperature fluctuations can be observed at decadal timescales. Most of the extreme flood events took place since the beginning of the 20(th) century with the strongest occurring in 2005. Our record thus suggests climate warming is favouring the occurrence of high magnitude torrential flood events in high-altitude catchments

Cost-effectiveness analysis of recombinant human follicle-stimulating hormone alfa(r-hFSH) and urinary highly purified menopausal gonadotropin (hMG) based on data from a large German registry

This was a retrospective real-world evidence analysis of the costs per live birth for reference recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa) versus highly purified urinary human menopausal gonadotropin (hMG-HP), based on data from a German in vitro fertilization registry (RecDate). Pregnancy and live birth rates from the RecDate real-world evidence study over three complete assisted reproductive technology (ART) cycles using the same gonadotropin drug were used as clinical inputs. Costs related to ART treatment and to drugs were obtained from public sources. Treatment with r-hFSH-alfa resulted in higher adjusted cumulative live birth rates versus hMG-HP after one (25.3% vs. 22.3%), two (30.9% vs. 27.5%), and three (31.9% vs. 28.6%) ART cycles. Costs per live birth were lower with r-hFSH-alfa versus hMG-HP after one (\u20ac17,938 vs. \u20ac20,054), two (\u20ac18,251 vs. \u20ac20,437), and three (\u20ac18,473 vs. \u20ac20,680) ART cycles. r-hFSH-alfa was found to be a cost-effective strategy compared with hMG-HP over three cycles

How to handle mortality when investigating length of hospital stay and time to clinical stability

<p>Abstract</p> <p>Background</p> <p>Hospital length of stay (LOS) and time for a patient to reach clinical stability (TCS) have increasingly become important outcomes when investigating ways in which to combat Community Acquired Pneumonia (CAP). Difficulties arise when deciding how to handle in-hospital mortality. Ad-hoc approaches that are commonly used to handle time to event outcomes with mortality can give disparate results and provide conflicting conclusions based on the same data. To ensure compatibility among studies investigating these outcomes, this type of data should be handled in a consistent and appropriate fashion.</p> <p>Methods</p> <p>Using both simulated data and data from the international Community Acquired Pneumonia Organization (CAPO) database, we evaluate two ad-hoc approaches for handling mortality when estimating the probability of hospital discharge and clinical stability: 1) restricting analysis to those patients who lived, and 2) assigning individuals who die the "worst" outcome (right-censoring them at the longest recorded LOS or TCS). Estimated probability distributions based on these approaches are compared with right-censoring the individuals who died at time of death (the complement of the Kaplan-Meier (KM) estimator), and treating death as a competing risk (the cumulative incidence estimator). Tests for differences in probability distributions based on the four methods are also contrasted.</p> <p>Results</p> <p>The two ad-hoc approaches give different estimates of the probability of discharge and clinical stability. Analysis restricted to patients who survived is conceptually problematic, as estimation is conditioned on events that happen <it>at a future time</it>. Estimation based on assigning those patients who died the worst outcome (longest LOS and TCS) coincides with the complement of the KM estimator based on the subdistribution hazard, which has been previously shown to be equivalent to the cumulative incidence estimator. However, in either case the time to in-hospital mortality is ignored, preventing simultaneous assessment of patient mortality in addition to LOS and/or TCS. The power to detect differences in underlying hazards of discharge between patient populations differs for test statistics based on the four approaches, and depends on the underlying hazard ratio of mortality between the patient groups.</p> <p>Conclusions</p> <p>Treating death as a competing risk gives estimators which address the clinical questions of interest, and allows for simultaneous modelling of both in-hospital mortality and TCS / LOS. This article advocates treating mortality as a competing risk when investigating other time related outcomes.</p

The health and economic burden of bloodstream infections caused by antimicrobial-susceptible and non-susceptible Enterobacteriaceae and <i>Staphylococcus aureus</i> in European hospitals, 2010 and 2011:a multicentre retrospective cohort study

We performed a multicentre retrospective cohort study including 606,649 acute inpatient episodes at 10 European hospitals in 2010 and 2011 to estimate the impact of antimicrobial resistance on hospital mortality, excess length of stay (LOS) and cost. Bloodstream infections (BSI) caused by third-generation cephalosporin-resistant Enterobacteriaceae (3GCRE), meticillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA) increased the daily risk of hospital death (adjusted hazard ratio (HR) = 1.80; 95% confidence interval (CI): 1.34-2.42, HR = 1.81; 95% CI: 1.49-2.20 and HR = 2.42; 95% CI: 1.66-3.51, respectively) and prolonged LOS (9.3 days; 95% CI: 9.2-9.4, 11.5 days; 95% CI: 11.5-11.6 and 13.3 days; 95% CI: 13.2-13.4, respectively). BSI with third-generation cephalosporin-susceptible Enterobacteriaceae (3GCSE) significantly increased LOS (5.9 days; 95% CI: 5.8-5.9) but not hazard of death (1.16; 95% CI: 0.98-1.36). 3GCRE significantly increased the hazard of death (1.63; 95% CI: 1.13-2.35), excess LOS (4.9 days; 95% CI: 1.1-8.7) and cost compared with susceptible strains, whereas meticillin resistance did not. The annual cost of 3GCRE BSI was higher than of MRSA BSI. While BSI with S. aureus had greater impact on mortality, excess LOS and cost than Enterobacteriaceae per infection, the impact of antimicrobial resistance was greater for Enterobacteriaceae

Effect of carbapenem resistance on outcomes of bloodstream infection caused by Enterobacteriaceae in low-income and middle-income countries (PANORAMA): a multinational prospective cohort study

Background Low-income and middle-income countries (LMICs) are under-represented in reports on the burden of antimicrobial resistance. We aimed to quantify the clinical effect of carbapenem resistance on mortality and length of hospital stay among inpatients in LMICs with a bloodstream infection due to Enterobacteriaceae. Methods The PANORAMA study was a multinational prospective cohort study at tertiary hospitals in Bangladesh, Colombia, Egypt, Ghana, India, Lebanon, Nepal, Nigeria, Pakistan, and Vietnam, recruiting consecutively diagnosed patients with carbapenem-susceptible Enterobacteriaceae (CSE) and carbapenem-resistant Entero-bacteriaceae (CRE) bloodstream infections. We excluded patients who had previously been enrolled in the study and those not treated with curative intent at the time of bloodstream infection onset. There were no age restrictions. Central laboratories in India and the UK did confirmatory testing and molecular characterisation, including strain typing. We applied proportional subdistribution hazard models with inverse probability weighting to estimate the effect of carbapenem resistance on probability of discharge alive and in-hospital death, and multistate modelling for excess length of stay in hospital. All patients were included in the analysis. Findings Between Aug 1, 2014, and June 30, 2015, we recruited 297 patients from 16 sites in ten countries: 174 with CSE bloodstream infection and 123 with CRE bloodstream infection. Median age was 46 years (IQR 15–61). Crude mortality was 20% (35 of 174 patients) for patients with CSE bloodstream infection and 35% (43 of 123 patients) for patients with CRE bloodstream infection. Carbapenem resistance was associated with an increased length of hospital stay (3·7 days, 95% CI 0·3–6·9), increased probability of in-hospital mortality (adjusted subdistribution hazard ratio 1·75, 95% CI 1·04–2·94), and decreased probability of discharge alive (0·61, 0·45–0·83). Multilocus sequence typing showed various clades, with marginal overlap between strains in the CRE and CSE clades. Interpretation Carbapenem resistance is associated with increased length of hospital stay and mortality in patients with bloodstream infections in LMICs. These data will inform global estimates of the burden of antimicrobial resistance and reinforce the need for better strategies to prevent, diagnose, and treat CRE infections in LMICs

Stabilizing cumulative incidence estimation of pregnancy outcome with delayed entries.

A pregnancy may end up with (at least) three possible events: live birth, spontaneous abortion, or elective termination, yielding a competing risks issue when studying an association between a risk factor and a pregnancy outcome. Cumulative incidences (probabilities to end up with the different outcomes depending on gestational age) can be estimated via the Aalen-Johansen estimate. Another issue is that women are usually not entering such an observational study from the first day of pregnancy, resulting in delayed entries. As in traditional survival analysis, this can be solved by considering "at risk" at a given gestational age only for those women who entered the study before that age. However, the number of women at risk at an early gestational age might be extremely low, such that the estimates of cumulative incidence may increase exaggeratedly at that age because of a single event. One solution to reduce the problem has been recently proposed in the literature, which is to ignore simply those early events, creating a small mean bias but enhancing stability of estimates. In the present paper, we propose an alternative computationally simple approach to tackle this problem that consists to postpone to later gestational ages (rather than to ignore) those early events. The two approaches are compared with respect to bias, stability, and sensitivity on the smoothing parameter via simulations reproducing realistic pregnancy scenarios, and are illustrated with data from a study on the effects of statins on pregnancy outcomes. We also outline that all three approaches are asymptotically equivalent