Human platelet lysate improves the growth and survival of cultured human pre-antral follicles.

RESEARCH QUESTION: How do platelet-rich plasma products like human platelet lysate (HPL) and umbilical cord plasma (UCP) affect the growth and survival of isolated human pre-antral follicles in vitro? DESIGN: Human pre-antral follicles (n = 724; mean diameter: 75 µm; range: 46-237 µm) were isolated from ovarian medulla donated by 14 patients undergoing unilateral oophorectomy for ovarian tissue cryopreservation. Follicles were encapsulated in 0.5% alginate and cultured for 8 days in media supplemented with 5% fetal bovine serum (FBS) (n = 171), 2.5% human serum albumin (HSA) (n = 159), 5% HPL (n = 223) or 5% UCP (n = 171). RESULTS: The survival probability was significantly higher in the group supplemented with HPL (80%) compared with the other three groups: FBS (54%, P < 0.001); HSA (63%, P = 0.004) and UCP (29%, P < 0.001). Surviving follicles in the UCP group had less defined follicular membranes and decompacted granulosa cell layers. The median growth of surviving follicles was significantly (P < 0.001) larger in the HPL group (73 µm) compared with any of the other three groups: HSA (43 µm); FBS (40 µm) UCP (54 µm). A descriptive analysis of follicular secretion of anti-Müllerian hormone and oestradiol did not reveal any difference between the groups. The detectability of follicular genes was high for AR (100%), AMHR2 (100%) and FSHR (76%), whereas few follicles expressed LHR (20%). CONCLUSION: Human platelet lysate significantly improved survival and growth of cultured human pre-antral follicles compared with FBS, HSA and UCP. The use of HPL is a valuable improvement to culture human pre-antral follicles but further studies will have to prove whether the superiority of HPL translates into better quality oocytes.

Treated periodontitis and recurrent events after first-time myocardial infarction: A Danish nationwide cohort study.

AIM: To investigate the association between previous periodontal treatment and recurrent events after first-time myocardial infarction (MI). MATERIALS AND METHODS: From the Danish nationwide registries, patients with first-time MI between 2000 and 2015 were divided into three groups according to oral health care within 1 year prior to first-time MI. A multiple logistic regression model provided adjusted odds ratios (ORs) with 95% confidence intervals (CIs) to assess the 3-year risk of major adverse cardiovascular events (MACE). RESULTS: A total of 103,949 patients were included. Patients with treated periodontitis (PD) prior to first-time MI had an adjusted 3-year risk of MACE similar to patients presumed periodontally healthy (OR 0.97 [95% CI 0.92-1.03]). Patients with no prior dental visits were significantly older, had more comorbidities and showed significantly increased adjusted 3-year risks of MACE (OR 1.47 [95% CI 1.42-1.52]), cardiovascular death (OR 1.71 [95% CI 1.64-1.78]) and heart failure (OR 1.13 [95% CI 1.07-1.20]) compared with patients presumed periodontally healthy. CONCLUSIONS: Patients with treated PD 1 year prior to first-time MI had a similar risk of recurrent cardiovascular events as patients presumed periodontally healthy. No dental visit prior to first-time MI was an independent risk factor for recurrent events.

Transplantation of initially rejected donor lungs using ex vivo lung perfusion: A 5-year experience.

BACKGROUND: Ex vivo lung perfusion (EVLP) is a method for the evaluation and reconditioning of high-risk donor lungs to increase the pool of potential donor lungs. METHODS: We reviewed all consecutive patients who received lung transplants from May 2012 to May 2017 with follow-up until July 2021. EVLP was used in lungs initially rejected due to inadequate oxygenation but without other contraindications. Lungs with improved oxygenation levels above the threshold were transplanted. The primary endpoint was the time to graft failure, which was defined as the time from surgery to death or re-transplantation, whichever occurred first. The secondary outcome was freedom from chronic lung allograft dysfunction. RESULTS: A total of 157 patients underwent transplantation during the study period. Thirty-nine patients received EVLP-treated donor lungs. Restricted mean graft survival time up to 7 years is 5.14 years for non-EVLP and 4.19 for EVLP, the difference being -0.95 (confidence interval [CI]-1.93 to 0.04, p = .059). The hazard ratio is 1.66 (CI 1.00-2.75, p = .046). Chronic lung allograft dysfunction was the highest contributor to mortality in both groups. There were significant differences in freedom from chronic lung allograft dysfunction at 12 and 24 months of follow-up (p = .005 and p = .030, respectively). Subgroup analyses revealed that the first patients who received EVLP in 2012-2013 had a substantially worse 5-year graft survival than those who received EVLP more recently in 2016-2017 (14.3% vs. 60.0%). For the latter, the 5-year graft survival was observed to be remarkably close to the non-EVLP group (60.8%). CONCLUSION: Long-term survival was significantly lower, and lung function was poorer among recipients in the EVLP group than in the non-EVLP group. However, the outcome of patients who received EVLP-treated lungs was observed to improve steadily after the first 2 years after EVLP was introduced in Denmark.

Adverse Events Associated With Coprescription of Phosphodiesterase Type 5 Inhibitors and Oral Organic Nitrates in Male Patients With Ischemic Heart Disease : A Case-Crossover Study.

BACKGROUND: Concomitant use of oral organic nitrates (nitrates) and phosphodiesterase type 5 (PDE5) inhibitors is contraindicated. OBJECTIVE: To measure temporal trends in the coprescription of nitrates and PDE5 inhibitors and to measure the association between cardiovascular outcomes and the coprescription of nitrates with PDE5 inhibitors. DESIGN: Case-crossover design. SETTING: Nationwide study of Danish patients from 2000 to 2018. PATIENTS: Male patients with International Classification of Diseases, 10th Revision (ICD-10) codes for ischemic heart disease (IHD), including those who had a continuing prescription for nitrates and a new, filled prescription for PDE5 inhibitors. MEASUREMENTS: Two composite outcomes were measured: 1) cardiac arrest, shock, myocardial infarction, ischemic stroke, or acute coronary arteriography and 2) syncope, angina pectoris, or drug-related adverse event. RESULTS: From 2000 to 2018, 249 541 male patients with IHD were identified. Of these, 42 073 patients had continuing prescriptions for nitrates. During this period, the prescription rate for PDE5 inhibitors in patients with IHD who were taking nitrates increased from an average of 0.9 prescriptions (95% CI, 0.5 to 1.2 prescriptions) per 100 persons per year in 2000 to 19.5 prescriptions (CI, 18.0 to 21.1 prescriptions) in 2018. No statistically significant association was found between the coprescription of nitrates with PDE5 inhibitors and the risk for either composite outcome (odds ratio [OR], 0.58 [CI, 0.28 to 1.13] for the first outcome and OR, 0.73 [CI, 0.40 to 1.32] for the second outcome). LIMITATION: An assumption was made that concurrently filled prescriptions for nitrates and PDE5 inhibitors equaled concomitant use. CONCLUSION: From 2000 to 2018, the use of PDE5 inhibitors increased 20-fold among Danish patients with IHD who were taking nitrates. A statistically significant association between concomitant use of these medications and cardiovascular adverse events could not be identified. PRIMARY FUNDING SOURCE: Ib Mogens Kristiansens Almene Fond and Helsefonden.

Gastrointestinal bleeding and the risk of colorectal cancer in anticoagulated patients with atrial fibrillation.

AIMS: Gastrointestinal bleeding (GI-bleeding) is frequent in patients with atrial fibrillation (AF) treated with oral anticoagulation (OAC) therapy. We sought to investigate to what extent lower GI-bleeding represents the unmasking of an occult colorectal cancer. METHODS AND RESULTS: A total of 125 418 Danish AF patients initiating OAC therapy were identified using Danish administrative registers. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risks of colorectal cancer in patients with and without lower GI-bleeding. During a maximum of 3 years of follow-up, we identified 2576 patients with lower GI-bleeding of whom 140 patients were subsequently diagnosed with colorectal cancer within the first year of lower GI-bleeding. In all age groups, we observed high risks of colorectal cancer after lower GI-bleeding. The absolute 1-year risk ranged from 3.7% [95% confidence interval (CI) 2.2-6.2] to 8.1% (95% CI 6.1-10.6) in the age groups ≤65 and 76-80 years of age, respectively. When comparing patients with and without lower GI-bleeding, we found increased risk ratios of colorectal cancer across all age groups with a risk ratio of 24.2 (95% CI 14.5-40.4) and 12.3 (95% CI 7.9-19.0) for the youngest and oldest age group of ≤65 and >85 years, respectively. CONCLUSION: In anticoagulated AF patients, lower GI-bleeding conferred high absolute risks of incident colorectal cancer. Lower GI-bleeding should not be dismissed as a benign consequence of OAC therapy but always examined for a potential underlying malignant cause.

On logistic regression with right censored data, with or without competing risks, and its use for estimating treatment effects.

Simple logistic regression can be adapted to deal with right-censoring by inverse probability of censoring weighting (IPCW). We here compare two such IPCW approaches, one based on weighting the outcome, the other based on weighting the estimating equations. We study the large sample properties of the two approaches and show that which of the two weighting methods is the most efficient depends on the censoring distribution. We show by theoretical computations that the methods can be surprisingly different in realistic settings. We further show how to use the two weighting approaches for logistic regression to estimate causal treatment effects, for both observational studies and randomized clinical trials (RCT). Several estimators for observational studies are compared and we present an application to registry data. We also revisit interesting robustness properties of logistic regression in the context of RCTs, with a particular focus on the IPCW weighting. We find that these robustness properties still hold when the censoring weights are correctly specified, but not necessarily otherwise.

Electrical cardioversion of atrial fibrillation and the risk of brady-arrhythmic events.

BACKGROUND: Electrical cardioversion (ECV) is a common procedure for terminating atrial fibrillation (AF). ECV is associated with brady-arrhythmic events, however, the age-specific risks of clinically significant brady-arrhythmic events are unknown. METHODS: Using Danish nationwide registers, we identified patients with AF at their first non-emergent ECV between 2005 and 2018 and estimated their 30-day risk of brady-arrhythmic events. Moreover, factors associated with increased risks of brady-arrhythmias were identified. Absolute risks were estimated using logistic regression models fitted with natural splines as well as standardization (G-formula). RESULTS: We identified 20,725 eligible patients with a median age of 66 years (IQR 60-72) and most males (73%). The 30-day risks of brady-arrhythmic events after ECV were highly dependent on age with estimated risks ranging from 0.5% (95% CI 0.2-1.7) and 1.2% (95% CI 0.99-1.5) to 2.7% (95% CI 2.1-3.3) and 5.1% (95% CI 2.6-9.7) in patients aged 40, 65, 80, and 90 years, respectively. Factors associated with brady-arrhythmias were generally related to cardiovascular disease (eg, ischemic heart disease, heart failure, valvular AF) or a history of syncope. We found no indications that pre-treatment with anti-arrhythmic drugs conferred increased risks of brady-arrhythmic events (standardized absolute risk difference -0.25% [95% CI -0.67 to 0.17]). CONCLUSIONS: ECV conferred clinically relevant 30-day risks of brady-arrhythmic events, especially in older patients. Anti-arrhythmic drug treatment was not found to increase the risk of brady-arrhythmias. Given the widespread use of ECV, these data should provide insights regarding the potential risks of brady-arrhythmic events.

A closed max-t test for multiple comparisons of areas under the ROC curve.

Comparing areas under the ROC curve (AUCs) is a popular approach to compare prognostic biomarkers. The aim of this paper is to present an efficient method to control the family-wise error rate when multiple comparisons are performed. We suggest to combine the max-t test and the closed testing procedures. We build on previous work on asymptotic results for ROC curves and on general multiple testing methods to efficiently take into account both the correlations between the test statistics and the logical constraints between the null hypotheses. The proposed method results in an uniformly more powerful procedure than both the single-step max-t test procedure and popular stepwise extensions of the Bonferroni procedure, such as Bonferroni-Holm. As demonstrated in this paper, the method can be applied in most usual contexts, including the time-dependent context with right censored data. We show how the method works in practice through a motivating example where we compare several psychometric scores to predict the t-year risk of Alzheimer's disease. The example illustrates several multiple testing settings and demonstrates the advantage of using the proposed methods over common alternatives. R code has been made available to facilitate the use of the methods by others.

Effect of long-term beta-blocker treatment following myocardial infarction among stable, optimally treated patients without heart failure in the reperfusion era: a Danish, nationwide cohort study.

AIMS: We aimed to investigate the long-term cardio-protective effect associated with beta-blocker (BB) treatment in stable, optimally treated myocardial infarction (MI) patients without heart failure (HF). METHODS AND RESULTS: Using nationwide registries, we included patients with first-time MI undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) during admission and treated with both acetyl-salicylic acid and statins post-discharge between 2003 and 2018. Patients with prior history of MI, prior BB use, or any alternative indication or contraindication for BB treatment were excluded. Follow-up began 3 months following discharge in patients alive, free of cardiovascular (CV) events or procedures. Primary outcomes were CV death, recurrent MI, and a composite outcome of CV events. We used adjusted logistic regression and reported standardized absolute risks and differences (ARD) 3 years after MI. Overall, 30 177 stable, optimally treated MI patients were included (58% acute PCI, 26% sub-acute PCI, 16% CAG without intervention). At baseline, 82% of patients were on BB treatment (median age 61 years, 75% male) and 18% were not (median age 62 years, 68% male). BB treatment was associated with a similar risk of CV death, recurrent MI, and the composite outcome of CV events compared with no BB treatment [ARD (95% confidence intervals)] correspondingly; 0.1% (-0.3% to 0.5%), 0.2% (-0.7% to 1.2%), and 1.2% (-0.2% to 2.7%). CONCLUSIONS: In this nationwide cohort study of stable, optimally treated MI patients without HF, we found no long-term effect of BB treatment on CV prognosis following the patients from 3 months to 3 years after MI admission.

Oral fluoroquinolones and risk of aortic or mitral regurgitation: a nationwide nested case-control study.

AIMS: Reports have suggested an increased risk of aortic and mitral regurgitation associated with oral fluoroquinolones (FQs) resulting in a safety warning published by the European Medicines Agency (EMA). However, these findings have not yet been replicated. METHODS AND RESULTS: Using Danish administrative registers, we conducted a nested case-control study in a nationwide cohort of individuals between 2005 and 2018. Cases were defined as the first occurrence of aortic or mitral regurgitation. Exposure of interest was the use of oral FQs. Hazard ratios (HRs) with 95% confidence intervals (95% CI) were obtained by fitting time-dependent Cox regression models, with penicillin V as comparator, to assess the association between FQ use and incident valvular regurgitation. We identified 38 370 cases of valvular regurgitation with 1 115 100 matched controls. FQ exposure was not significantly associated with increased rates of aortic or mitral regurgitation (HR 1.02, 95% CI 0.95-1.09) compared with penicillin V users. Investigating the cumulative defined daily doses (cDDD) of FQs yielded similar results with no significant association between increasing FQ use and valvular regurgitation (e.g. HR 1.08, 95% CI 0.95-1.23 for cDDD >10 compared with cDDD 1-5). These results were consistent across several analyses including a cohort of patients with hypertension and using a case definition based on valvular surgical interventions. CONCLUSIONS: In a nationwide nested case-control study, FQs were not significantly associated with increased rates of valvular regurgitation. Our findings do not support a possible causal connection between FQ exposure and incident valvular regurgitation.

Increased risk of neonatal complications and infections in children of kidney-transplanted women: A nationwide controlled cohort study.

Information related to short- and long-term risks of children born to kidney-transplanted women remains limited. With the aim of investigating the risk of neonatal complications, and the short- and long-term risk of infections in offspring of kidney-transplanted women, all children born to kidney-transplanted women in Denmark from 1964 to 2016 were identified in a nationwide retrospective matched cohort study. A total of 124 children of kidney-transplanted women were identified and matched on gender, birth year, and number of siblings at birth 1:10 with children born to nontransplanted women identified in the Danish general population. Prevalence of low birth weight (37.9%, risk ratio [RR] = 12.61; 95% confidence interval [CI], 8.5-18.5), premature birth (46.0%, RR = 11.32; 95% CI, 8.1-15.7) and malformations (11.3%, RR = 1.98; 95% CI, 1.2-3.4) was increased in children of kidney-transplanted women compared with controls. Similarly, prevalence of hospitalization due to infection was increased during the first year of life (21.0%, RR = 1.94; 95% CI, 1.3-2.8), from age 1 to 5 (34.2%, RR = 1.89; 95% CI, 1.4-2.5), and overall (41.9%, RR = 1.67; 95% CI, 1.3-2.1). The risk of infection was also higher in children of kidney-transplanted mothers born preterm or with low birth weight compared with similar controls. In conclusion, risk of neonatal complications, malformations, and both early and late infection were increased in children born to kidney-transplanted women.

The c-index is not proper for the evaluation of $t$-year predicted risks.

We show that the widely used concordance index for time to event outcome is not proper when interest is in predicting a $t$-year risk of an event, for example 10-year mortality. In the situation with a fixed prediction horizon, the concordance index can be higher for a misspecified model than for a correctly specified model. Impropriety happens because the concordance index assesses the order of the event times and not the order of the event status at the prediction horizon. The time-dependent area under the receiver operating characteristic curve does not have this problem and is proper in this context.

A covariate-specific time-dependent receiver operating characteristic curve for correlated survival data.

Several studies for the clinical validity of circulating tumor cells (CTCs) in metastatic breast cancer were conducted showing that it is a prognostic biomarker of overall survival. In this work, we consider an individual patient data meta-analysis for nonmetastatic breast cancer to assess the discrimination of CTCs regarding the risk of death. Data are collected in several centers and present correlated failure times for subjects of the same center. However, although the covariate-specific time-dependent receiver operating characteristic (ROC) curve has been widely used for assessing the performance of a biomarker, there is no methodology yet that can handle this specific setting with clustered censored failure times. We propose an estimator for the covariate-specific time-dependent ROC curves and area under the ROC curve when clustered failure times are detected. We discuss the assumptions under which the estimators are consistent and their interpretations. We assume a shared frailty model for modeling the effect of the covariates and the biomarker on the outcome in order to account for the cluster effect. A simulation study was conducted and it shows negligible bias for the proposed estimator and a nonparametric one based on inverse probability censoring weighting, while a semiparametric estimator, ignoring the clustering, is markedly biased. Finally, in our application to breast cancer data, the estimation of the covariate-specific area under the curves illustrates that the CTCs discriminate better patients with inflammatory tumor than patients with noninflammatory tumor, with respect to their risk of death.

Oral anticoagulation among atrial fibrillation patients with anaemia: an observational cohort study.

AIMS: To investigate the risk of stroke/thromboembolism (TE) and major bleeding associated with anaemia among patients with atrial fibrillation (AF). Also, to assess the effects of oral anticoagulation (OAC) and time in therapeutic range (TTR) with vitamin K antagonists according to level of haemoglobin (Hb). METHODS AND RESULTS: Through administrative registry databases, we identified all Danish patients diagnosed with AF from 1997 to 2012. We included 18 734 AF patients with recent available data on Hb. Multiple Cox regression analyses were used to estimate hazard ratios and to compute standardized absolute 1-year risks of stroke/TE and major bleeding. Among included patients, 3796 (20%) had mild anaemia (Hb 6.83-7.45 mmol/L for women and Hb 6.83-8.03 mmol/L for men) and 2562 (14%) had moderate/severe anaemia (Hb <6.83 mmol/L). Moderate/severe anaemia was associated with increased risk of major bleeding and 9.1% lower median TTR compared with no anaemia. Use of OAC was associated with reduced risk of stroke/TE among patients without anaemia [standardized absolute 1-year difference -2.5%, 95% confidence interval (CI) -3.8 to -1.7%] or with mild anaemia (-2.3%, 95% CI -2.8 to -1.8%), but not with moderate/severe anaemia, (0.03%, -1.8 to +2.8%, interaction P = 0.01). Oral anticoagulation was associated with a 5.3% (95% CI 2.1-8.7%) increased standardized absolute risk of major bleeding among AF patients with moderate/severe anaemia. CONCLUSION: Anaemia was common in patients with AF and associated with major bleeding and lower TTR. Oral anticoagulation was associated with more major bleeding, but no reduction in risk of stroke/TE among AF patients with moderate/severe anaemia.

On evaluating how well a biomarker can predict treatment response with survival data.

One of the objectives of personalized medicine is to take treatment decisions based on a biomarker measurement. Therefore, it is often interesting to evaluate how well a biomarker can predict the response to a treatment. To do so, a popular methodology consists of using a regression model and testing for an interaction between treatment assignment and biomarker. However, the existence of an interaction is not sufficient for a biomarker to be predictive. It is only necessary. Hence, the use of the marker-by-treatment predictiveness curve has been recommended. In addition to evaluate how well a single continuous biomarker predicts treatment response, it can further help to define an optimal threshold. This curve displays the risk of a binary outcome as a function of the quantiles of the biomarker, for each treatment group. Methods that assume a binary outcome or rely on a proportional hazard model for a time-to-event outcome have been proposed to estimate this curve. In this work, we propose some extensions for censored data. They rely on a time-dependent logistic model, and we propose to estimate this model via inverse probability of censoring weighting. We present simulations results and three applications to prostate cancer, liver cirrhosis, and lung cancer data. They suggest that a large number of events need to be observed to define a threshold with sufficient accuracy for clinical usefulness. They also illustrate that when the treatment effect varies with the time horizon which defines the outcome, then the optimal threshold also depends on this time horizon.

Confidence intervals for the cumulative incidence function via constrained NPMLE.

The cumulative incidence function (CIF) displays key information in the competing risks setting, which is common in medical research. In this article, we introduce two new methods to compute non-parametric confidence intervals for the CIF. First, we introduce non-parametric profile-likelihood confidence intervals. The method builds on constrained non-parametric maximum likelihood estimation (NPMLE), for which we derive closed-form formulas. This method can be seen as an extension of that of Thomas and Grunkemeier (J Am Stat Assoc 70:865-871, 1975) to the competing risks setting, when the CIF is of interest instead of the survival function. Second, we build on constrained NPMLE to introduce constrained bootstrap confidence intervals. This extends an interesting approach introduced by Barber and Jennison (Biometrics 52:430-436, 1999) to the competing risks setting. A simulation study illustrates how these methods can perform as compared to benchmarks implemented in popular software. The results suggest that more accurate confidence intervals than usual Wald-type ones can be obtained in the case of small to moderate sample sizes and few observed events. An application to melanoma data is provided for illustration purpose.

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.

Decline in incidence of sudden cardiac death in the young: a 10-year nationwide study of 8756 deaths in Denmark.

AIMS: Sudden cardiac death in the young (SCDY) accounts for a significant proportion of deaths among the young. The aim of this nationwide study was to examine temporal changes in incidence and causes of SCDY in Denmark in 2000-2009. During this 10-year period, several public and private health initiatives were undertaken to decrease morbidity and mortality in Denmark. METHODS AND RESULTS: All deaths among persons aged 1-35 years in Denmark in 2000-2009 (23.7 million person-years) were included. Death certificates, autopsy reports, discharge summaries, and data from nationwide administrative registries were used to identify SCDY cases. Sudden cardiac death in the young incidence rates were age-adjusted and sex-adjusted using direct standardization. Temporal changes in standardized SCDY incidence rates were reported as average annual percent changes. In the 10-year study period, there were 8756 deaths, of which we identified 635 (7%) SCDY cases. For these SCDY cases, median age at death was 29 years and 68% were men. Standardized incidence of SCDY decreased from 3.1 per 100 000 person-years in 2000 [95% confidence interval (CI) 2.4-3.8] to 2.5 per 100 000 person-years in 2009 (95% CI 1.9-3.2). This corresponds to an average annual percent change of -3.0% (95% CI -5.8 to -0.1). The distribution of major causes of SCDY did not change significantly throughout the study period. CONCLUSION: Incidence of SCDY decreased significantly from 2000 through 2009 in Denmark with an average annual percent change of -3%. Further research is needed to elucidate underlying causes of this development.

The Wally plot approach to assess the calibration of clinical prediction models.

A prediction model is calibrated if, roughly, for any percentage x we can expect that x subjects out of 100 experience the event among all subjects that have a predicted risk of x%. Typically, the calibration assumption is assessed graphically but in practice it is often challenging to judge whether a "disappointing" calibration plot is the consequence of a departure from the calibration assumption, or alternatively just "bad luck" due to sampling variability. We propose a graphical approach which enables the visualization of how much a calibration plot agrees with the calibration assumption to address this issue. The approach is mainly based on the idea of generating new plots which mimic the available data under the calibration assumption. The method handles the common non-trivial situations in which the data contain censored observations and occurrences of competing events. This is done by building on ideas from constrained non-parametric maximum likelihood estimation methods. Two examples from large cohort data illustrate our proposal. The 'wally' R package is provided to make the methodology easily usable.