Search

Individual participant data (IPD) meta-analysis provides important opportunities to study interaction and effect modification for which individual studies often lack power. While previous meta-analyses have commonly focused on multiplicative interaction, additive interaction holds greater relevance for public health and may in certain contexts better reflect biological interaction. Methodological literature on interaction in IPD meta-analysis does not cover additive interaction for models including binary or time-to-event outcomes. We aimed to describe how the Relative Excess Risk due to Interaction (RERI) and other measures of additive interaction or effect modification can be validly estimated within two-stage IPD meta-analysis. First, we explain why direct pooling of study-level RERI estimates may lead to invalid results. Next, we propose a three-step procedure to estimate additive interaction: 1) estimate effects of both exposures and their product term on the outcome within each individual study; 2) pool study-specific estimates using multivariate meta-analysis; 3) estimate an overall RERI and 95% confidence interval based on the pooled effect estimates. We illustrate this procedure by investigating interaction between depression and smoking and risk of smoking-related cancers using data from the PSYchosocial factors and Cancer (PSY-CA) consortium. We discuss implications of this procedure, including the application in meta-analysis based on published data., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Aims: Recently, a genetic variant-specific prediction model for phospholamban (PLN) p.(Arg14del)-positive individuals was developed to predict individual major ventricular arrhythmia (VA) risk to support decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts major VA risk from baseline data, but iterative evaluation of major VA risk may be warranted considering that the risk factors for major VA are progressive. Our aim is to evaluate the diagnostic performance of the PLN p.(Arg14del) risk model at 3-year follow-up., Methods and Results: We performed a landmark analysis 3 years after presentation and selected only patients with no prior major VA. Data were collected of 268 PLN p.(Arg14del)-positive subjects, aged 43.5 ± 16.3 years, 38.9% male. After the 3 years landmark, subjects had a mean follow-up of 4.0 years (± 3.5 years) and 28 (10%) subjects experienced major VA with an annual event rate of 2.6% [95% confidence interval (CI) 1.6-3.6], defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. The PLN p.(Arg14del) risk score yielded good discrimination in the 3 years landmark cohort with a C-statistic of 0.83 (95% CI 0.79-0.87) and calibration slope of 0.97., Conclusion: The PLN p.(Arg14del) risk model has sustained good model performance up to 3 years follow-up in PLN p.(Arg14del)-positive subjects with no history of major VA. It may therefore be used to support decision-making for primary prevention ICD implantation not merely at presentation but also up to at least 3 years of follow-up., Competing Interests: Conflict of interest: The UMCG, which employs several of the authors, has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc., Novo Nordisk, and Roche. R.A.deB. has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche. T.G. has had speaker engagements with Bristol Myers Squibb. M.Y.C.vd.H. and A.A.M.W. report grants from PLN foundation, grants from CVON Netherlands Heart Foundation (PREDICT2) and ZonMw (PSIDER-Heart) during this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Summary: In clinical and biomedical research, multiple high-dimensional datasets are nowadays routinely collected from omics and imaging devices. Multivariate methods, such as Canonical Correlation Analysis (CCA), integrate two (or more) datasets to discover and understand underlying biological mechanisms. For an explorative method like CCA, interpretation is key. We present a sparse CCA method based on soft-thresholding that produces near-orthogonal components, allows for browsing over various sparsity levels, and permutation-based hypothesis testing. Our soft-thresholding approach avoids tuning of a penalty parameter. Such tuning is computationally burdensome and may render unintelligible results. In addition, unlike alternative approaches, our method is less dependent on the initialization. We examined the performance of our approach with simulations and illustrated its use on real cancer genomics data from drug sensitivity screens. Moreover, we compared its performance to Penalized Matrix Analysis (PMA), which is a popular alternative of sparse CCA with a focus on yielding interpretable results. Compared to PMA, our method offers improved interpretability of the results, while not compromising, or even improving, signal discovery., Availability and Implementation: The software and simulation framework are available at https://github.com/nuria-sv/toscca., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press.)

Aims: Hypertension is an important global health burden with major differences in prevalence among ethnic minorities compared with host populations. Longitudinal research on ethnic differences in blood pressure (BP) levels provides the opportunity to assess the efficacy of strategies aimed at mitigating gaps in hypertension control. In this study, we assessed the change in BP levels over time in a multi-ethnic population-based cohort in Amsterdam, the Netherlands., Methods and Results: We used baseline and follow-up data from HELIUS to assess differences in BP over time between participants of Dutch, South Asian Surinamese, African Surinamese, Ghanaian, Moroccan, and Turkish descent. Baseline data were collected between 2011 and 2015 and follow-up data between 2019 and 2021. The main outcome was ethnic differences in systolic BP (SBP) over time determined by linear mixed models adjusted for age, sex, and use of antihypertensive medication. We included 22 109 participants at baseline, from which 10 170 participants had complete follow-up data. The mean follow-up time was 6.3 (1.1) years. Compared with the Dutch population, the mean SBP increased significantly more from baseline to follow-up in Ghanaians [1.78 mmHg, 95% confidence interval (CI) 0.77-2.79], Moroccans (2.06 mmHg, 95% CI 1.23-2.90), and the Turkish population (1.30 mmHg, 95% CI 0.38-2.22). Systolic blood pressure differences were in part explained by differences in body mass index (BMI). No differences in SBP trajectory were present between the Dutch and Surinamese population., Conclusion: Our findings indicate a further increase of ethnic differences in SBP among Ghanaian, Moroccan, and Turkish populations compared with the Dutch reference population that are in part attributable to differences in BMI., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Familial hypercholesterolaemia (FH) predisposes children to the early initiation of atherosclerosis and is preferably diagnosed by DNA analysis. Yet, in many children with a clinical presentation of FH, no mutation is found. Adult data show that high levels of lipoprotein(a) [Lp(a)] may underlie a clinical presentation of FH, as the cholesterol content of Lp(a) is included in conventional LDL cholesterol measurements. As this is limited to adult data, Lp(a) levels in children with and without (clinical) FH were evaluated., Methods and Results: Children were eligible if they visited the paediatric lipid clinic (1989-2020) and if Lp(a) measurement and DNA analysis were performed. In total, 2721 children (mean age: 10.3 years) were included and divided into four groups: 1931 children with definite FH (mutation detected), 290 unaffected siblings/normolipidaemic controls (mutation excluded), 108 children with probable FH (clinical presentation, mutation not detected), and 392 children with probable non-FH (no clinical presentation, mutation not excluded). In children with probable FH, 32% were found to have high Lp(a) [geometric mean (95% confidence interval) of 15.9 (12.3-20.6) mg/dL] compared with 10 and 10% [geometric means (95% confidence interval) of 11.5 (10.9-12.1) mg/dL and 9.8 (8.4-11.3) mg/dL] in children with definite FH (P = 0.017) and unaffected siblings (P = 0.002), respectively., Conclusion: Lp(a) was significantly higher and more frequently elevated in children with probable FH compared with children with definite FH and unaffected siblings, suggesting that high Lp(a) may underlie the clinical presentation of FH when no FH-causing mutation is found. Performing both DNA analysis and measuring Lp(a) in all children suspected of FH is recommended to assess possible LDL cholesterol overestimation related to increased Lp(a)., Competing Interests: Conflicts of interest: A.W. reports research support for pharmaceutical trials of lipid modification agents from Amgen, Regeneron, and Novartis. B.A.H. and A.W. received a research grant from Silence Therapeutics plc that partially funded this work. Other authors have no conflicts of interest to declare., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Lipoprotein(a) [Lp(a)] is a causal and independent risk factor for cardiovascular disease (CVD). People with elevated Lp(a) are often prescribed statins as they also often show elevated low-density lipoprotein cholesterol (LDL-C) levels. While statins are well-established in lowering LDL-C, their effect on Lp(a) remains unclear. We evaluated the effect of statins compared to placebo on Lp(a) and the effects of different types and intensities of statin therapy on Lp(a)., Methods and Results: We conducted a systematic review and meta-analysis of randomized trials with a statin and placebo arm. Medline and EMBASE were searched until August 2019. Quality assessment of studies was done using Cochrane risk-of-bias tool (RoB 2). Mean difference of absolute and percentage changes of Lp(a) in the statin vs. the placebo arms were pooled using a random-effects meta-analysis. We compared effects of different types and intensities of statin therapy using subgroup- and network meta-analyses. Certainty of the evidence was determined using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Overall, 39 studies (24 448 participants) were included. Mean differences (95% confidence interval) of absolute and percentage changes in the statin vs. the placebo arms were 1.1 mg/dL (0.5-1.6, P < 0.0001) and 0.1% (-3.6% to 4.0%, P = 0.95), respectively (moderate-certainty evidence). None of the types of statins changed Lp(a) significantly compared to placebo (very low- to high-certainty evidence), as well as intensities of statin therapy (low- to moderate-certainty evidence)., Conclusion: Statin therapy does not lead to clinically important differences in Lp(a) compared to placebo in patients at risk for CVD. Our findings suggest that in these patients, statin therapy will not change Lp(a)-associated CVD risk., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Automated external defibrillators (AEDs) are placed in public, but the majority of out-of-hospital cardiac arrests (OHCA) occur at home., Methods and Results: In residential areas, 785 AEDs were placed and 5735 volunteer responders were recruited. For suspected OHCA, dispatchers activated nearby volunteer responders with text messages, directing two-thirds to an AED first and one-third directly to the patient. We analysed survival (primary outcome) and neurologically favourable survival to discharge, time to first defibrillation shock, and cardiopulmonary resuscitation (CPR) before Emergency Medical Service (EMS) arrival of patients in residences found with ventricular fibrillation (VF), before and after introduction of this text-message alert system. Survival from OHCAs in residences increased from 26% to 39% {adjusted relative risk (RR) 1.5 [95% confidence interval (CI): 1.03-2.0]}. RR for neurologically favourable survival was 1.4 (95% CI: 0.99-2.0). No CPR before ambulance arrival decreased from 22% to 9% (RR: 0.5, 95% CI: 0.3-0.7). Text-message-responders with AED administered shocks to 16% of all patients in VF in residences, while defibrillation by EMS decreased from 73% to 39% in residences (P < 0.001). Defibrillation by first responders in residences increased from 22 to 40% (P < 0.001). Use of public AEDs in residences remained unchanged (6% and 5%) (P = 0.81). Time from emergency call to defibrillation decreased from median 11.7 to 9.3 min; mean difference -2.6 (95% CI: -3.5 to -1.6)., Conclusion: Introducing volunteer responders directed to AEDs, dispatched by text-message was associated with significantly reduced time to first defibrillation, increased bystander CPR and increased overall survival for OHCA patients in residences found with VF., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Heart failure is the main threat to long-term health in adults with transposition of the great arteries (TGA) corrected by an atrial switch operation (AtrSO). Current guidelines refrain from recommending heart failure medication in TGA-AtrSO, as there is insufficient data to support the hypothesis that it is beneficial. Medication is therefore prescribed based on personal judgements. We aimed to evaluate medication use in TGA-AtrSO patients and examine the association of use of renin-angiotensin-aldosterone system (RAAS) inhibitors and β-blockers with long-term survival., Methods and Results: We identified 150 TGA-AtrSO patients [median age 30 years (interquartile range 25-35), 63% male] included in the CONCOR registry from five tertiary medical centres with subsequent linkage to the Dutch Dispensed Drug Register for the years 2006-2014. Use of RAAS inhibitors, β-blockers, and diuretics increased with age, from, respectively, 21% [95% confidence interval (CI) 14-40], 12% (95% CI 7-21), and 3% (95% CI 2-7) at age 25, to 49% (95% CI 38-60), 51% (95% CI 38-63), and 41% (95% CI 29-54) at age 45. Time-varying Cox marginal structural models that adjusted for confounding medication showed a lower mortality risk with use of RAAS inhibitors and β-blockers in symptomatic patients [hazard ratio (HR) = 0.13 (95% CI 0.03-0.73); P = 0.020 and HR = 0.12 (95% CI 0.02-0.17); P = 0.019, respectively]. However, in the overall cohort, no benefit of RAAS inhibitors and β-blockers was seen [HR = 0.93 (95% CI 0.24-3.63); P = 0.92 and HR = 0.98 (0.23-4.17); P = 0.98, respectively]., Conclusion: The use of heart failure medication is high in TGA-AtrSO patients, although evidence of its benefit is limited. This study showed lower risk of mortality with use of RAAS inhibitors and β-blockers in symptomatic patients only. These findings can direct future guidelines, supporting use of RAAS inhibitors and β-blockers in symptomatic, but not asymptomatic patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: This study aims to improve risk stratification for primary prevention implantable cardioverter defibrillator (ICD) implantation by developing a new mutation-specific prediction model for malignant ventricular arrhythmia (VA) in phospholamban (PLN) p.Arg14del mutation carriers. The proposed model is compared to an existing PLN risk model., Methods and Results: Data were collected from PLN p.Arg14del mutation carriers with no history of malignant VA at baseline, identified between 2009 and 2020. Malignant VA was defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. A prediction model was developed using Cox regression. The study cohort consisted of 679 PLN p.Arg14del mutation carriers, with a minority of index patients (17%) and male sex (43%), and a median age of 42 years [interquartile range (IQR) 27-55]. During a median follow-up of 4.3 years (IQR 1.7-7.4), 72 (10.6%) carriers experienced malignant VA. Significant predictors were left ventricular ejection fraction, premature ventricular contraction count/24 h, amount of negative T waves, and presence of low-voltage electrocardiogram. The multivariable model had an excellent discriminative ability {C-statistic 0.83 [95% confidence interval (CI) 0.78-0.88]}. Applying the existing PLN risk model to the complete cohort yielded a C-statistic of 0.68 (95% CI 0.61-0.75)., Conclusion: This new mutation-specific prediction model for individual VA risk in PLN p.Arg14del mutation carriers is superior to the existing PLN risk model, suggesting that risk prediction using mutation-specific phenotypic features can improve accuracy compared to a more generic approach., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: This study was performed to develop and externally validate prediction models for appropriate implantable cardioverter-defibrillator (ICD) shock and mortality to identify subgroups with insufficient benefit from ICD implantation., Methods and Results: We recruited patients scheduled for primary prevention ICD implantation and reduced left ventricular function. Bootstrapping-based Cox proportional hazards and Fine and Gray competing risk models with likely candidate predictors were developed for all-cause mortality and appropriate ICD shock, respectively. Between 2014 and 2018, we included 1441 consecutive patients in the development and 1450 patients in the validation cohort. During a median follow-up of 2.4 (IQR 2.1-2.8) years, 109 (7.6%) patients received appropriate ICD shock and 193 (13.4%) died in the development cohort. During a median follow-up of 2.7 (IQR 2.0-3.4) years, 105 (7.2%) received appropriate ICD shock and 223 (15.4%) died in the validation cohort. Selected predictors of appropriate ICD shock were gender, NSVT, ACE/ARB use, atrial fibrillation history, Aldosterone-antagonist use, Digoxin use, eGFR, (N)OAC use, and peripheral vascular disease. Selected predictors of all-cause mortality were age, diuretic use, sodium, NT-pro-BNP, and ACE/ARB use. C-statistic was 0.61 and 0.60 at respectively internal and external validation for appropriate ICD shock and 0.74 at both internal and external validation for mortality., Conclusion: Although this cohort study was specifically designed to develop prediction models, risk stratification still remains challenging and no large group with insufficient benefit of ICD implantation was found. However, the prediction models have some clinical utility as we present several scenarios where ICD implantation might be postponed., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Preliminary evidence from animal and human studies shows that gut microbiota composition and levels of microbiota-derived metabolites, including short-chain fatty acids (SCFAs), are associated with blood pressure (BP). We hypothesized that faecal microbiota composition and derived metabolites may be differently associated with BP across ethnic groups., Methods and Results: We included 4672 subjects (mean age 49.8 ± 11.7 years, 52% women) from six different ethnic groups participating in the HEalthy Life In an Urban Setting (HELIUS) study. The gut microbiota was profiled using 16S rRNA gene amplicon sequencing. Associations between microbiota composition and office BP were assessed using machine learning prediction models. In the subgroups with the largest associations, faecal SCFA levels were compared in 200 subjects with lower or higher systolic BP. Faecal microbiota composition explained 4.4% of the total systolic BP variance. Best predictors for systolic BP included Roseburia spp., Clostridium spp., Romboutsia spp., and Ruminococcaceae spp. Explained variance of the microbiota composition was highest in Dutch subjects (4.8%), but very low in South-Asian Surinamese, African Surinamese, Ghanaian, Moroccan and Turkish descent groups (explained variance <0.8%). Faecal SCFA levels, including acetate (P < 0.05) and propionate (P < 0.01), were lower in young Dutch participants with low systolic BP., Conclusions: Faecal microbiota composition is associated with BP, but with strongly divergent associations between ethnic groups. Intriguingly, while Dutch participants with lower BP had higher abundances of several SCFA-producing microbes, they had lower faecal SCFA levels. Intervention studies with SCFAs could provide more insight in the effects of these metabolites on BP., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: The COMPARE trial showed a small but significant beneficial effect of 3-year losartan treatment on aortic root dilatation rate in adults with Marfan syndrome (MFS). However, no significant effect was found on clinical endpoints, possibly due to a short follow-up period. The aim of the current study was therefore to investigate the long-term clinical outcomes after losartan treatment., Methods and Results: In the original COMPARE study (inclusion 2008-2009), adult patients with MFS (n = 233) were randomly allocated to either the angiotensin-II receptor blocker losartan® on top of regular treatment (β-blockers in 71% of the patients) or no additional medication. After the COMPARE trial period of 3 years, study subjects chose to continue their losartan medication or not. In a median follow-up period of 8 years, 75 patients continued losartan medication, whereas 78 patients, originally allocated to the control group, never used losartan after inclusion. No differences existed between baseline characteristics of the two groups except for age at inclusion [losartan 34 (interquartile range, IQR 26-43) years, control 41 (IQR 30-52) years; P = 0.031], and β-blocker use (losartan 81%, control 64%; P = 0.022). A pathological FBN1 mutation was present in 76% of patients and 58% of the patients were male. Clinical endpoints, defined as all-cause mortality, aortic dissection/rupture, elective aortic root replacement, reoperation, and vascular graft implantation beyond the aortic root, were compared between the two groups. A per-patient composite endpoint was also analysed. Five deaths, 14 aortic dissections, 23 aortic root replacements, 3 reoperations, and 3 vascular graft implantations beyond the aortic root occurred during follow-up. Except for aortic root replacement, all endpoints occurred in patients with an operated aortic root. Patients who used losartan during the entire follow-up period showed a reduced number of events compared to the control group (death: 0 vs. 5, P = 0.014; aortic dissection: 3 vs. 11, P = 0.013; elective aortic root replacement: 10 vs. 13, P = 0.264; reoperation: 1 vs. 2, P = 0.463; vascular graft implantations beyond the aortic root 0 vs. 3, P = 0.071; and composite endpoint: 14 vs. 26, P = 0.019). These results remained similar when corrected for age and β-blocker use in a multivariate analysis., Conclusion: These results suggest a clinical benefit of combined losartan and β-blocker treatment in patients with MFS., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

In nephrology, a great deal of information is measured repeatedly in patients over time, often alongside data on events of clinical interest. In this introductory article we discuss how these two types of data can be simultaneously analysed using the joint model (JM) framework, illustrated by clinical examples from nephrology. As classical survival analysis and linear mixed models form the two main components of the JM framework, we will also briefly revisit these techniques., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Genetic risk factors can provide insight into susceptibility for acute pancreatitis (AP) and disease progression towards (infected) necrotizing pancreatitis and persistent organ failure. The aim of the study was to undertake a systematic review of the genetic evidence for AP., Methods: Online databases (MEDLINE, Embase, BIOSIS, Web of Science, Cochrane Library) were searched to 8 February 2018. Studies that reported on genetic associations with AP susceptibility, severity and/or complications were eligible for inclusion. Meta-analyses were performed of variants that were reported by at least two data sources. Venice criteria and Bayesian false-discovery probability were applied to assess credibility., Results: Ninety-six studies reporting on 181 variants in 79 genes were identified. In agreement with previous meta-analyses, credible associations were established for SPINK1 (odds ratio (OR) 2·87, 95 per cent c.i. 1·89 to 4·34), IL1B (OR 1·23, 1·06 to 1·42) and IL6 (OR 1·64, 1·15 to 2·32) and disease risk. In addition, two novel credible single-nucleotide polymorphisms were identified in Asian populations: ALDH2 (OR 0·48, 0·36 to 0·64) and IL18 (OR 1·47, 1·18 to 1·82). Associations of variants in TNF, GSTP1 and CXCL8 genes with disease severity were identified, but were of low credibility., Conclusion: Genetic risk factors in genes related to trypsin activation and innate immunity appear to be associated with susceptibility to and severity of AP., (© 2019 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Background: Palliative systemic therapy can prolong life and reduce tumor-related symptoms for patients with advanced esophagogastric cancer. However, side effects of treatment could negatively affect health-related quality of life (HRQoL). Our aim was to review the literature and conduct a meta-analysis to examine the effect of palliative systemic therapy on HRQoL., Methods: EMBASE, Medline, and Central were searched for phase II/III randomized controlled trials until April 2018 investigating palliative systemic therapy and HRQoL. Meta-analysis was performed on baseline and follow-up summary values of global health status (GHS) and other European Organisation for Research and Treatment of Cancer scales. A clinically relevant change and difference of 10 points (scale 0-100) was set to assess the course of HRQoL over time within treatment arms as well as between arms., Results: We included 43 randomized controlled trials (N = 13 727 patients). In the first-line and beyond first-line treatment setting, pooled baseline GHS mean estimates were 54.6 (95% confidence interval = 51.9 to 57.3) and 57.9 (95% confidence interval = 55.7 to 60.1), respectively. Thirty-nine (81.3%) treatment arms showed a stable GHS over the course of time. Anthracycline-based triplets, fluoropyrimidine-based doublets without cisplatin, and the addition of trastuzumab to chemotherapy were found to have favorable HRQoL outcomes. HRQoL benefit was observed for taxane monotherapy and several targeted agents over best supportive care beyond first line., Conclusions: Patients reported impaired GHS at baseline and generally remained stable over time. Anthracycline-based triplets and fluoropyrimidine-based doublets without cisplatin may be preferable first-line treatment options regarding HRQoL for HER2-negative disease. Taxanes and targeted agents could provide HRQoL benefit beyond first line compared with best supportive care., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The host immune response is characterized by a complex interplay of signal-specific cellular transcriptional responses. The magnitude of the immune response is dependent on the strength of the external stimulus. Knowledge on leukocyte transcriptional responses altered in response to different stimulus dosages in man is lacking. Here, we sought to identify leukocyte transcriptional signatures dependent on LPS dose in humans. Healthy human volunteers were administered 1 ng/kg (n = 7), 2 ng/kg (n = 6), or 4 ng/kg (n = 7) LPS intravenously. Blood was collected before (pre-LPS) and 4 h after LPS administration. Total RNA was analyzed by microarrays and generalized linear models. Pathway analysis was performed by using Ingenuity pathway analysis. Leukocyte transcriptomes altered per LPS dosage were predominantly shared, with 47% common signatures relative to pre-LPS. A univariate linear model identified a set of 3736 genes that exhibited a dependency on differing LPS dosages. Neutrophil, monocyte, and lymphocyte counts explained 38.9% of the variance in the LPS dose-dependent gene set. A multivariate linear model including leukocyte composition delineated a set of 295 genes with a dependency on LPS dose. Evaluation of the 295 gene signature in patients with sepsis due to abdominal infections showed significant correlations. Promoter regions of the LPS dose gene set were enriched for YY1, EGR1, ELK1, GABPA, KLF4, and REL transcription factor binding sites. Intravenous injection of 1, 2, or 4 ng/kg LPS was accompanied by both shared and distinct leukocyte transcriptional alterations. These data may assist in assessing the severity of the insult in patients with abdominal sepsis., (© 2019 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals, Inc. on behalf of Society for Leukocyte Biology.)

Aims: To assess medication use in adult congenital heart disease (ACHD) patients compared to the age- and sex-matched general population, identify patterns of pharmacotherapy, and analyse associations between pharmacotherapy and adverse outcomes in ACHD., Methods and Results: Data of 14 138 ACHD patients from the CONCOR registry [35 (24-48) years, 49% male] and age- and sex-matched referents (1:10 ratio) were extracted from the Dutch Dispensed Drug Register for the years 2006-14. Adult congenital heart disease patients had more cardiovascular and non-cardiovascular drugs than referents (median 3 vs. 1, P < 0.001). Polypharmacy, defined as ≥5 dispensed drug types yearly, was present in 30% of ACHD and 15% of referents {odds ratio [OR] = 2.47 [95% confidence interval (CI) 2.39-2.54]}. Polypharmacy was independently associated with female sex [OR = 1.92 (95% CI 1.88-1.96)], older age [for men: OR = 2.3/10 years (95% CI 2.2-2.4) and for women: OR = 1.6/10 years (95% CI 1.5-1.6); Pinteraction < 0.001], and ACHD severity [mild: OR = 2.51 (95% CI 2.40-2.61), moderate: OR = 3.22 (95% CI 3.06-3.40), severe: OR = 4.87 (95% CI 4.41-5.38)]. Cluster analysis identified three subgroups with distinct medication patterns; a low medication use group (8-year cumulative survival: 98%), and a cardiovascular and comorbidity group with lower survival (92% and 95%, respectively). Cox regression revealed a strong association between polypharmacy and mortality [hazard ratio (HR) = 3.94 (95% CI 3.22-4.81)], corrected for age, sex, and defect severity. Polypharmacy also increased the risk of hospitalization for adverse drug events [HR = 4.58 (95% CI 2.04-10.29)]., Conclusion: Both cardiovascular and non-cardiovascular medication use is high in ACHD with twice as much polypharmacy compared with the matched general population. Patients with polypharmacy had a four-fold increased risk of mortality and adverse drug events. Recognition of distinct medication patterns can help identify patients at highest risk. Drug regimens need repeating evaluation to assess the appropriateness of all prescriptions. More high-quality studies are needed to improve ACHD care with more evidence-based pharmacotherapy., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The global prevalence of obesity in women keeps increasing. The preconception period may be a window of opportunity to improve lifestyle, reduce obesity and improve cardiometabolic health. This study assessed the effect of a preconception lifestyle intervention on long-term cardiometabolic health in two randomized controlled trials (RCTs)., Methods: Participants of the LIFEstyle and RADIEL preconception lifestyle intervention studies with a baseline body mass index (BMI) ≥29 kg/m2 were eligible for this follow-up study. Both studies randomized between a lifestyle intervention targeting physical activity, diet and behaviour modification or usual care. We assessed cardiometabolic health 6 years after randomization., Results: In the LIFEstyle study (n = 111) and RADIEL study (n = 39), no statistically significant differences between the intervention and control groups were found for body composition, blood pressure, arterial stiffness, fasting glucose, homeostasis model assessment of insulin resistance, HbA1c, lipids and high sensitive C-reactive protein levels 6 years after randomization. Participants of the LIFEstyle study who successfully lost ≥5% bodyweight or reached a BMI <29 kg/m2 during the intervention (n = 22, [44%]) had lower weight (-8.1 kg; 99% CI [-16.6 to -0.9]), BMI (-3.3 kg/m2; [-6.5 to -0.8]), waist circumference (-8.2 cm; [-15.3 to -1.3]), fasting glucose (-0.5 mmol/L; [-1.1 to -0.0]), HbA1c (-4.1 mmol/mol; [-9.1 to -0.8]), and higher HDL-C (0.3 mmol/L; [0.1-0.5]) compared with controls., Conclusion: We found no evidence of improved cardiometabolic health 6 years after a preconception lifestyle intervention among overweight and obese women in two RCTs. Women who successfully lost weight during the intervention had better cardiometabolic health 6 years later, emphasizing the potential of successful preconception lifestyle improvement., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Public Health Association.)

Aims: We sought to determine subtypes of patients with heart failure (HF) with a distinct clinical profile and treatment response, using a wide range of biomarkers from various pathophysiological domains., Methods and Results: We performed unsupervised cluster analysis using 92 established cardiovascular biomarkers to identify mutually exclusive subgroups (endotypes) of 1802 patients with HF and reduced ejection fraction (HFrEF) from the BIOSTAT-CHF project. We validated our findings in an independent cohort of 813 patients. Based on their biomarker profile, six endotypes were identified. Patients with endotype 1 were youngest, less symptomatic, had the lowest N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lowest risk for all-cause mortality or hospitalization for HF. Patients with endotype 4 had more severe symptoms and signs of HF, higher NT-proBNP levels and were at highest risk for all-cause mortality or hospitalization for HF [hazard ratio (HR) 1.4; 95% confidence interval (CI) 1.1-1.8]. Patients with endotypes 2, 3, and 5 were better uptitrated to target doses of beta-blockers (P < 0.02 for all). In contrast to other endotypes, patients with endotype 5 derived no potential survival benefit from uptitration of angiotensin-converting enzyme-inhibitor/angiotensin-II receptor blocker and beta-blockers (Pinteraction <0.001). Patients with endotype 2 (HR 1.29; 95% CI 1.10-1.42) experienced possible harm from uptitration of beta-blockers in contrast to patients with endotype 4 and 6 that experienced benefit (Pinteraction for all <0.001). Results were strikingly similar in the independent validation cohort., Conclusion: Using unsupervised cluster analysis, solely based on biomarker profiles, six distinct endotypes were identified with remarkable differences in characteristics, clinical outcome, and response to uptitration of guideline directed medical therapy.

Aims: The clinical correlates and consequences of atrial fibrillation (AF) might be different between heart failure with reduced vs. preserved ejection fraction (HFrEF vs. HFpEF). Biomarkers may provide insights into underlying pathophysiological mechanisms of AF in these different heart failure (HF) phenotypes., Methods and Results: We performed a retrospective analysis of the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF), which was an observational cohort. We studied 2152 patients with HFrEF [ejection fraction (EF < 40%)], of which 1419 were in sinus rhythm (SR) and 733 had AF. Another 524 patients with HFpEF (EF ≥50%) were studied, of which 286 in SR and 238 with AF. For the comparison of biomarker profiles, 92 cardiovascular risk markers were measured (Proseek® Olink Cardiovascular III panel). The circulating risk marker pattern observed in HFrEF was different than the pattern in HFpEF: in HFrEF, AF was associated with higher levels of 77 of 92 (84%) risk markers compared to SR; whereas in HFpEF, many more markers were higher in SR than in AF. Over a median follow-up of 21 months, AF was associated with increased mortality risk [multivariable hazard ratio (HR) of 1.27; 95% confidence interval (CI) 1.09-1.48, P = 0.002]; there was no significant interaction between heart rhythm and EF group on outcome., Conclusion: In patients with HFrEF, the presence of AF was associated with a homogeneously elevated cardiovascular risk marker profile. In contrast, in patients with HFpEF, the presence of AF was associated with a more scattered risk marker profile, suggesting differences in underlying pathophysiological mechanisms of AF in these HF phenotypes.

Motivation: Recent technological developments have enabled the possibility of genetic and genomic integrated data analysis approaches, where multiple omics datasets from various biological levels are combined and used to describe (disease) phenotypic variations. The main goal is to explain and ultimately predict phenotypic variations by understanding their genetic basis and the interaction of the associated genetic factors. Therefore, understanding the underlying genetic mechanisms of phenotypic variations is an ever increasing research interest in biomedical sciences. In many situations, we have a set of variables that can be considered to be the outcome variables and a set that can be considered to be explanatory variables. Redundancy analysis (RDA) is an analytic method to deal with this type of directionality. Unfortunately, current implementations of RDA cannot deal optimally with the high dimensionality of omics data (p≫n). The existing theoretical framework, based on Ridge penalization, is suboptimal, since it includes all variables in the analysis. As a solution, we propose to use Elastic Net penalization in an iterative RDA framework to obtain a sparse solution., Results: We proposed sparse redundancy analysis (sRDA) for high dimensional omics data analysis. We conducted simulation studies with our software implementation of sRDA to assess the reliability of sRDA. Both the analysis of simulated data, and the analysis of 485 512 methylation markers and 18,424 gene-expression values measured in a set of 55 patients with Marfan syndrome show that sRDA is able to deal with the usual high dimensionality of omics data., Availability and Implementation: http://uva.csala.me/rda., Contact: a.csala@amc.uva.nl., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Aims: Adult congenital heart disease (ACHD) predisposes to infective endocarditis (IE). Surgical advancements have changed the ACHD population, whereas associated prosthetic material may constitute additional IE targets. We aimed to prospectively determine contemporary incidence, risk factors, and predictors of IE in a nationwide ACHD cohort, focusing on the presence of prosthetics., Methods and Results: We identified 14 224 patients prospectively followed in the CONCOR ACHD registry (50.5% female, median age 33.6years). IE incidence was determined using Poisson regression, risk factors and predictors using Cox regression. Overall incidence was 1.33 cases/1000 person-years (124 cases in 93 562 person-years). For risk-factor analysis, presence of prosthetics was forced-as separate time-updated variables for specific prosthetics-into a model with baseline characteristics univariably associated with IE. Valve-containing prosthetics were independently associated with greater risk both short- and long term after implantation [0-6 months: hazard ratio (HR) = 17.29; 7.34-40.70, 6-12 months: HR = 15.91; 6.76-37.45, beyond 12 months: HR = 5.26; 3.52-7.86], non-valve-containing prosthetics, including valve repair, only in the first 6 months after implantation (HR = 3.34; 1.33-8.41), not thereafter. A prediction model was derived and validated using bootstrapping techniques. Independent predictors of IE were baseline valve-containing prosthetics, main congenital heart defect, multiple defects, previous IE, and sex. The model had fair discriminative ability and provided accurate predictions up to 10 years., Conclusions: This study provides IE incidence estimates, and determinants of IE risk in a nationwide ACHD cohort. Our findings, essentially informing IE prevention guidelines, indicate valve-containing prosthetics as a main determinant of IE risk whereas other prosthetics, including valve-repair, are not associated with increased risk long term after implantation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Introduction: Despite clear guidelines recommendations, most patients with heart failure and reduced ejection-fraction (HFrEF) do not attain guideline-recommended target doses. We aimed to investigate characteristics and for treatment-indication-bias corrected clinical outcome of patients with HFrEF that did not reach recommended treatment doses of ACE-inhibitors/Angiotensin receptor blockers (ARBs) and/or beta-blockers., Methods and Results: BIOSTAT-CHF was specifically designed to study uptitration of ACE-inhibitors/ARBs and/or beta-blockers in 2516 heart failure patients from 69 centres in 11 European countries who were selected if they were suboptimally treated while initiation or uptitration was anticipated and encouraged. Patients who died during the uptitration period (n = 151) and patients with a LVEF > 40% (n = 242) were excluded. Median follow up was 21 months. We studied 2100 HFrEF patients (76% male; mean age 68 ±12), of which 22% achieved the recommended treatment dose for ACE-inhibitor/ARB and 12% of beta-blocker. There were marked differences between European countries. Reaching <50% of the recommended ACE-inhibitor/ARB and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50-99% of the recommended ACE-inhibitor/ARB and/or beta-blocker dose had comparable risk of death and/or heart failure hospitalization to those reaching ≥100%. Patients not reaching recommended dose because of symptoms, side effects and non-cardiac organ dysfunction had the highest mortality rate (for ACE-inhibitor/ARB: HR 1.72; 95% CI 1.43-2.01; for beta-blocker: HR 1.70; 95% CI 1.36-2.05)., Conclusion: Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Aims: Sudden cardiac death (SCD) is a major cause of mortality in adults with congenital heart disease (CHD). Several risk factors for SCD including conduction disturbances and ventricular dysfunction have been described previously. However, electrocardiogram (ECG) and echocardiographic parameters may change over time, and the predictive value of such temporal changes, rather than their point estimates, for SCD remains unknown., Methods and Results: This was a retrospective case-control study in adults with CHD and proven or presumed SCD and matched controls. Data were obtained from three databases including 25 000 adults with CHD. Sequential measurements were performed on electrocardiograms and echocardiograms. Ventricular function was assessed by echocardiography and graded on a four-point ordinal scale: 1, normal [ejection fraction (EF) ≥50%]; 2, mildly impaired (EF 40-49%); 3, moderately impaired (EF 30-39%); and 4, severely impaired (EF < 30%). Overall, 131 SCDs (mean age 36 ± 14 years, 67% male) and 260 controls (mean age 37 ± 13 years, 63% male) were included. At baseline, median QRS duration was 108 ms (range 58-168 ms) in SCDs and 97 ms (range 50-168 ms) in controls and increased over time at a rate of 1.6 ± 0.5 vs. 0.5 ± 0.2 ms/year in SCDs and controls, respectively (P = 0.011). QT dispersion at baseline was 61 ms (range 31-168 ms) in SCDs and 50 ms (range 21-129 ms) in controls. QT dispersion increased at a rate of 1.1 ± 0.4 ms/year in SCD victims and decreased at a rate of 0.2 ± 0.2 ms/year in controls (P = 0.004). Increase of QRS duration ≥5 ms/year was associated with an increased risk of SCD [OR 1.9, 95% confidence interval (CI) 1.1-3.3, P = 0.013]. Change from any baseline systemic ventricular function (normal, mild, or moderately impaired) to severe ventricular dysfunction over time was associated with the highest risk of SCD (OR 16.9, 95% CI 1.8-120.1, P = 0.008)., Conclusion: In adults with CHD, QRS duration and ventricular dysfunction progress over time. Progression of QRS duration and the rate of impairment of ventricular function served to identify those at increased risk of SCD., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Aims: The aorta in Marfan syndrome (MFS) patients is variably affected. We investigated the assumed genotype-effect on protein production as a risk factor for a severe aortic phenotype in adult MFS patients., Methods and Results: We collected clinical and genetic data from all 570 adults with MFS who had been included in the Dutch CONgenital CORvitia registry since the start in 2001. Mean age was 36.5 ± 13.5 years (51.2% male, 28.9% prior aortic surgery, 8.2% prior aortic dissection). Patients were prospectively followed for a mean duration of 8.2 ± 3.1 years. Men had more frequently aortic surgery at baseline (38.0 vs. 19.4%, P < 0.001) and during follow-up (24.0 vs. 15.1%, P = 0.008) compared with women. After 10-year follow-up cumulative survival was 93.8% and dissection-free survival was 84.2%. We found a pathogenic FBN1 mutation in 357 patients, of whom 146 patients (40.9%) were positive for a mutation causing haploinsufficiency (reduced fibrillin-1 protein) and 211 (59.1%) for a mutation leading to a DN effect (abnormal fibrillin-1 protein). Corrected for age, sex, and previous aortic complications, patients with a haploinsufficient (HI) mutation had a 2.5-fold increased risk for cardiovascular death (hazard ratio, HR: 2.5, 95% CI: 1.0-6.1, P = 0.049), a 2.4-fold increased risk for the combined endpoint comprising death and dissection (HR: 2.4, 95% CI: 1.4-4.2, P < 0.001) and a 1.6-fold increased risk for any aortic complication compared with patients with a DN mutation (HR: 1.6, 95% CI 1.1-2.3, P = 0.014)., Conclusion: Marfan syndrome patients with an HI mutation are at increased risk for cardiovascular death and aortic dissection compared with patients with a DN mutation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Genotyping increases the accuracy of a clinical score (based on pretreatment age, goiter size, FT4, TBII) for predicting recurrence of Graves' hyperthyroidism after a course of antithyroid drugs: a prospective study.

Aims: Particular atherosclerotic risk factors may differ in their association with atherosclerosis across vascular territories. Few studies have compared the associations between multiple risk factors and cardiovascular disease (CVD) manifestations in one population. We studied the strength of the associations between traditional risk factors including coronary artery disease (CAD), ischaemic and haemorrhagic stroke, abdominal aortic aneurysms (AAAs), and peripheral arterial disease (PAD)., Methods and Results: This analysis included 21 798 participants of the EPIC-Norfolk population study, without previous CVD. Events were defined as hospitalization or mortality, coded using ICD-10. The associations between the risk factors, such as low-density lipoprotein cholesterol, systolic blood pressure (SBP), and smoking, and the various CVD manifestations were compared using competing risk analyses. During 12.1 years, 3087 CVD events were recorded. The associations significantly differed across CVD manifestations. Low-density lipoprotein cholesterol was strongly associated with CAD [adjusted hazard rate (aHR) highest vs. lowest quartile 1.63, 95% CI 1.44-1.86]. Systolic blood pressure was a strong risk factor for PAD (aHR highest vs. lowest quartile 2.95, 95% CI 1.78-4.89) and ischaemic stroke (aHR highest vs. lowest quartile 2.48, 95% CI 1.55-3.97), but not for AAA. Smoking was strongly associated with incident AAA (aHR current vs. never 7.66, 95% CI 4.50-13.04) and PAD (aHR current vs. never 4.66, 95% CI 3.29-6.61), but not with haemorrhagic stroke., Conclusion: The heterogeneity in the risk factor-CVD associations supports the concept of pathophysiological differences between atherosclerotic CVD manifestations and could have implications for CVD prevention., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: The identification of sex differences in the prognosis of adults with a secundum atrial septal defect (ASD2) could help tailor their clinical management, as it has in other cardiovascular diseases. We investigated whether disparity between the sexes exists in long-term outcome of adult ASD2 patients., Methods and Results: Patients with ASD2 classified as the primary defect were selected from the Dutch national registry of adult congenital heart disease. Survival stratified by sex was compared with a sex-matched general population. In a total of 2207 adult patients (mean age at inclusion 44.8 years, 33.0% male), 102 deaths occurred during a cumulative follow-up of 13 584 patient-years. Median survival was 79.7 years for men and 85.6 years for women with ASD2. Compared with the age- and sex-matched general population, survival was lower for male, but equal for female patients (P = 0.015 and 0.766, respectively). Logistic regression analyses showed that men had a higher risk of conduction disturbances (OR = 1.63; 95% CI, 1.22-2.17) supraventricular dysrhythmias (OR = 1.41; 1.12-1.77), cerebrovascular thromboembolic events (OR = 1.53; 1.10-2.12), and heart failure (OR = 1.91; 1.06-3.43)., Conclusion: In contrast to women, adult men with an ASD2 have worse survival than a sex-matched general population. Male patients also have a greater risk of morbidity during adult life. Sex disparity in survival and morbidity suggests the need for a sex-specific clinical approach towards these patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Streptococcus pneumoniae (pneumococcus) is a major human pathogen causing pneumonia, sepsis and bacterial meningitis. Using a clinical phenotype based approach with bacterial whole-genome sequencing we identified pneumococcal arginine biosynthesis genes to be associated with outcome in patients with pneumococcal meningitis. Pneumococci harboring these genes show increased growth in human blood and cerebrospinal fluid (CSF). Mouse models of meningitis and pneumonia showed that pneumococcal strains without arginine biosynthesis genes were attenuated in growth or cleared, from lung, blood and CSF. Thus, S. pneumoniae arginine synthesis genes promote growth and virulence in invasive pneumococcal disease.

Aim: Patients with Marfan syndrome have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. Treatment with losartan, an angiotensin-II receptor-1 blocker, may reduce aortic dilatation rate in Marfan patients., Methods and Results: In this multicentre, open-label, randomized controlled trial with blinded assessments, we compared losartan treatment with no additional treatment in operated and unoperated adults with Marfan syndrome. The primary endpoint was aortic dilatation rate at any predefined aortic level after 3 years of follow-up, as determined by magnetic resonance imaging. A total of 233 participants (47% female) underwent randomization to either losartan (n = 116) or no additional treatment (n = 117). Aortic root dilatation rate after 3.1 ± 0.4 years of follow-up was significantly lower in the losartan group than in controls (0.77 ± 1.36 vs. 1.35 ± 1.55 mm, P = 0.014). Aortic dilatation rate in the trajectory beyond the aortic root was not significantly reduced by losartan. In patients with prior aortic root replacement, aortic arch dilatation rate was significantly lower in the losartan group when compared with the control group (0.50 ± 1.26 vs. 1.01 ± 1.31 mm, P = 0.033). No significant differences in separate clinical endpoints or the composite endpoint (aortic dissection, elective aortic surgery, cardiovascular death) between the groups could be demonstrated., Conclusion: In adult Marfan patients, losartan treatment reduces aortic root dilatation rate. After aortic root replacement, losartan treatment reduces dilatation rate of the aortic arch.

Study Question: Can mixture survival models help distinguish infertility from subfertility in couples with an unexplained unfulfilled child wish?, Summary Answer: Mixture models estimated that 47% of the couples were infertile; female age and previous pregnancy were significantly related to infertility, whereas duration of child wish was associated with a longer time to pregnancy for subfertile couples., What Is Known Already: To differentiate between couples who require assisted conception and couples who still have good chances of natural, i.e. unassisted, conception, several prediction models of natural conception have been developed. Prognostic factors in these models are usually assessed by Cox proportional hazard models that cannot differentiate between couples with an unfulfilled child wish who are subfertile, i.e. have reduced ability to conceive naturally, and couples who are really infertile, i.e. are completely unable to conceive naturally. We evaluated whether a mixture survival model can make such a distinction., Study Design, Size, Duration: Consecutive couples presenting at the fertility clinics of 38 centres in the Netherlands between January 2002 and February 2004 joined a prospective cohort study. Of the 7860 couples in the cohort, 3917 couples met our inclusion criteria. The median follow-up was 219 days, with a maximum of 5 years., Participants, Setting, Methods: Couples had to present with an unexplained cause of an unfulfilled child wish. A mixture model was used to estimate the proportion of couples who were infertile and the time to pregnancy for the subfertile couples., Main Results and the Role of Chance: During the follow-up, 794 couples conceived naturally. The mixture model estimated that 47% [95% confidence interval (CI): 33-56%] of couples were infertile, despite the absence of objective factors indicating a cause for infertility. Of the evaluated prognostic factors, female age, duration of child wish, previous pregnancy, semen quality, BMI and cycle length, female age [odds ratio (OR): 1.11, 95% CI: 1.03-1.19] and previous pregnancy (0.22, 95% CI: 0.07-0.67) were significant predictors of infertility. Among subfertile couples, a longer duration of a child wish (FFR: 0.72, 95% CI: 0.61-0.85) was a significant prognostic factor for time to pregnancy. In the Cox models, all variables except BMI were significant predictors of time to pregnancy., Limitations, Reasons for Caution: The mixture model had limited power due to a low number of couples at the end of the follow-up period. Mixture model analyses on external, long-term follow-up data are necessary to validate our results., Wider Implications of the Findings: Mixture models could be a useful tool in selecting couples who require assisted reproductive technology because the effects of prognostic factors can be subdivided into effects on the fraction of infertile couples and effects on the time to pregnancy for subfertile couples, which is not possible in conventional models., Study Funding/competing Interest(s): This study was supported by grant 945/12/002 from ZonMw, the Netherlands Organization for Health Research and Development, The Hague, the Netherlands.

The long-term treatment of human immunodeficiency virus (HIV)-infected children with combination antiretroviral therapy (cART) requires assessment of potential adverse effects, such as osteoporosis. Longitudinal data on bone mineral density (BMD) in HIV-infected children showed that cumulative treatment with cART had a positive impact on BMD over time.

Objectives: In chronic thromboembolic pulmonary hypertension (CTEPH), right ventricular (RV) dysfunction is associated with increased morbidity and mortality following pulmonary endarterectomy. Plasma brain natriuretic peptide (BNP) levels were previously shown to correlate with RV (dys)function. We hypothesized that BNP can be used as a non-invasive biomarker to identify patients at 'high risk' for postoperative morbidity and mortality., Methods: We studied the postoperative outcome in 73 consecutive patients. Patients were divided into three groups based on previously determined cut-off levels: BNP <11.5, indicating normal RV function (ejection fraction [EF] ≥45%), BNP >48.5 pmol/l, indicating RV dysfunction (right ventricular ejection fraction <30%) and BNP 11.5-48.5 pmol/l. Postoperative 'bad outcome' was defined as the presence of either residual pulmonary hypertension (PH) or (all-cause) mortality., Results: Plasma BNP >48.5 pmol/l was shown to be an independent predictor of 'bad outcome'. Compared with BNP <11.5 pmol/l, BNP >48.5 pmol/l identified patients at higher risk for (all-cause) mortality (17 vs 0%; P = 0.009) and residual PH (56 vs 20%; P < 0.004). Also, the durations of mechanical ventilation and intensive care unit stay were significantly longer in patients with BNP >48.5 pmol/ml., Conclusions: Plasma BNP levels may be of use as a non-invasive biomarker reflecting RV dysfunction, next to other well-recognized (invasive) parameters, for better preoperative risk stratification of CTEPH patients.

Background: Prediction of natural conception in subfertile couples can help to differentiate between couples who should have immediate treatment and couples who can aim for natural conception for some time. Natural conception rates are often estimated using standard techniques such as Kaplan-Meier or Cox proportional hazard models. These estimates can be biased by incorrect handling of data from women who start assisted reproductive technology therapy before the end of the follow-up period. This paper discusses the validity and the impact of the assumption of non-informative censoring as used in the Kaplan-Meier and Cox models., Methods: In a cohort of 5360 subfertile couples with suspected tubal pathology, the probability of natural conception and the prognostic value of additional tests for tubal pathology were estimated using traditional methods and with a competing risks analysis., Results: The estimated probability of natural conception within 3 years was almost 2-fold higher when assuming non-informative censoring compared with the competing risks model, 41 versus 22%. The prognostic value of tests was more conservative using the competing risks model than with the traditional methods, the fecundity rate ratio for Chlamydia antibody testing was 0.72 versus 0.67, for hysterosalpingography, 0.83 versus 0.71 and for diagnostic laparoscopy, 0.89 versus 0.74., Conclusions: Given the improbable validity of the non-informative censoring assumption, the predictions of natural conception and of the prognostic value of tests are likely to be overestimated by the traditional analytic methods. We suggest the use of competing risks models as an alternative, more conservative, form of analysis when predicting natural conception and evaluating prognostic fertility tests.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by bidirectional or polymorphic ventricular arrhythmias under conditions of increased sympathetic activity in young patients with structurally normal hearts. Patients with CPVT are at high risk of developing life-threatening ventricular arrhythmias when untreated. A wide variety of arrhythmic event rates on conventional therapy, with β-blockers as the cornerstone, has been reported. Here, we systematically review all available studies describing the efficacy of β-blocker therapy for prevention of arrhythmic events in CPVT. Because of heterogeneity between the studies, a random-effects meta-analysis model was used to assess the efficacy of β-blocker therapy in preventing any arrhythmic event [syncope, aborted cardiac arrest (ACA), and sudden cardiac death (SCD)], near-fatal arrhythmic events (ACA and SCD), and fatal arrhythmic events. Eleven studies including 403 patients, of whom 354 (88%) had a β-blocker prescribed, were identified. Mean follow-up ranged from 20 months to 8 years. Estimated 8-year arrhythmic, near-fatal, and fatal event rates were 37.2% [95% confidence interval (CI): 16.6-57.7], 15.3% (95% CI: 7.4-23.3), and 6.4% (95% CI: 3.2-9.6), respectively. In addition, we review the recent developments in alternate chronic treatment options for CPVT patients, including calcium channel blockers, flecainide, left cardiac sympathetic denervation, and implantable cardioverter defibrillators. A new treatment strategy is proposed, including a stepwise addition of the alternate treatment options to β-blockers in patients who do not respond sufficiently to this first-line therapy. Finally, future developments in chronic treatment options and acute treatment options of ventricular arrhythmias are discussed.

Background: Pneumocystis jiroveci pneumonia (PCP) is an important cause of morbidity and mortality in renal transplant recipients (RTRs). Chemoprophylaxis with trimethoprim/sulphamethoxazole is recommended during the early post-transplantation period, but the optimal duration has not been determined and a main drawback of chemoprophylaxis is the development of resistance of the commensal faecal flora. A cluster outbreak of PCP occurred in our outpatient Renal Transplant Unit. We aimed to investigate risk factors for PCP in RTRs to determine who should receive long-term chemoprophylaxis., Methods: In a case-control study, we investigated common demographic variables and immunological parameters. Nine PCP cases diagnosed between August 2006 and April 2007 were matched with 18 control patients, who did not develop PCP, received their transplant in the same time-period and had a similar follow-up period with a comparable immunosuppressive drug regimen., Results: The median time from transplantation to PCP was 19 months. We observed no significant differences in gender, age, donor type or number of rejections. In PCP cases, the median lymphocyte count just before PCP diagnosis was 0.49 (0.26-0.68), which was significantly reduced compared to the control patients after a similar follow-up period (median 1.36, 0.59-3.04, P = 0.002). This lymphocytopaenia was chronic and existed in most patients already for many months. CD4(+) T-cell counts were also significantly reduced in the PCP cases. We found no difference in the Th1, Th2 and Th17 subsets between PCP cases and control patients., Conclusion: Long-term prophylactic therapy for PCP may be indicated for RTR with persistent severe lymphocytopaenia.

Background: Incidence rates of renal replacement therapy (RRT) for end-stage renal disease vary considerably worldwide. This study examines the independent association between the general population, health care system and renal service characteristics and RRT incidence rates., Methods: RRT incidence data (2003-2005) were obtained from renal registries; general population age and health and macroeconomic indices were collected from secondary sources. Renal service organization and resource data were obtained through interviews and questionnaires. Linear regression models were built to establish the factors independently associated with RRT incidence, stratified by the Human Development Index where required. False discovery rate (FDR) correction was adjusted for multiple testing., Results: Across the 46 countries (population 1.25 billion), RRT incidence rates ranged from 12 to 455 (median 130) per million population. Gross domestic product (GDP) per capita [incidence rate ratio (IRR): 1.02 per $1000 increase, P(FDR) = 0.047], percentage of GDP spent on health care (IRR: 1.11 per % increase, P(FDR) = 0.006) and dialysis facility reimbursement rate relative to GDP (IRR: 0.76 per GDP per capita-sized increase in reimbursement rate, P(FDR) = 0.007) were independently associated with RRT incidence. In more developed countries, the private for-profit share of haemodialysis facilities was also associated with higher incidence (IRR: 1.009 per % increase, P(FDR) = 0.003)., Conclusions: Macroeconomic and renal service factors are more often associated with RRT incidence rates than measured demographic or general population health status factors.

Introduction: Postorgasmic illness syndrome (POIS) is a combination of local allergic symptoms and transient flu-like illness. In this study, the investigators propose five preliminary criteria to establish the diagnosis., Aim: To describe the clinical details in 45 males being suspected of having POIS and to test an immunogenic hypothesis as the underlying mechanism of their presentations., Methods: Forty-five males were studied according to standardized protocol, including neuropsychiatric and medical sexological evaluations; their complaints were categorized using their own words, and their self-perceived intravaginal ejaculation latency time (IELT). Skin-prick testing with autologous diluted semen in 33 men were also performed., Main Outcome Measures: Clinical features of POIS including self-perceived IELTs and the results of skin-prick testing with autologous diluted seminal fluid., Results: Of the 45 included men, 33 subjects consented with skin-prick testing. Of them, 29 (88%) men had a positive skin-prick test with their own (autologous) semen, and four had a negative test. In 87% of men, POIS symptoms started within 30 minutes after ejaculation. Complaints of POIS were categorized in seven clusters of symptoms, e.g., general, flu-like, head, eyes, nose, throat, and muscles. Local allergic reactions of eyes and nose were reported in 44% and 33% of subjects, a flu-like syndrome in 78% of subjects, exhaustion and concentration difficulties in 80% and 87% of subjects. Of all subjects, 58% had an atopic constitution. Lifelong premature ejaculation, defined as self-perceived IELT < 1 minute, was reported in 25 (56%) of subjects., Conclusions: The combination of allergic and systemic flu-like reactions post-ejaculation together with a positive skin-prick test in the majority of males underscores the hypothesis of an "immunogenic" etiology of POIS, e.g., that POIS is caused by Type-1 and Type-IV allergy to the males' own semen, as soon it is triggered by ejaculation., (© 2011 International Society for Sexual Medicine.)

Motoneuron disease is a term encompassing three phenotypes defined largely by the balance of upper versus lower motoneuron involvement, namely amyotrophic lateral sclerosis, primary lateral sclerosis and progressive muscular atrophy. However, neuroradiological and pathological findings in these phenotypes suggest that degeneration may exceed the neuronal system upon which clinical diagnosis is based. To further delineate the phenotypes within the motoneuron disease spectrum, this controlled study assessed the upper- and extra-motoneuron white matter involvement in cohorts of patients with motoneuron disease phenotypes shortly after diagnosis by comparing diffusion tensor imaging data of the different cohorts to those of healthy controls and directly between the motoneuron disease phenotypes (n = 12 for each cohort). Furthermore, we acquired follow-up data 6 months later to evaluate fractional anisotropy changes over time. Combined use of diffusion tensor tractography of the corticospinal tract and whole-brain voxel-based analysis allowed for comparison of the sensitivity of these techniques to detect white matter involvement in motoneuron disease. The voxel-based analysis demonstrated varying extents of white matter involvement in different phenotypes of motoneuron disease, albeit in quite similar anatomical locations. In general, fractional anisotropy reductions were modest in progressive muscular atrophy and most extensive in primary lateral sclerosis. The most extensive patterns of fractional anisotropy reduction were observed over time in the voxel-based analysis, indicating progressive extra-motor white matter degeneration in limb- and bulbar onset amyotrophic lateral sclerosis and in progressive muscular atrophy. The observation of both upper motor and extra-motoneuron involvement in all phenotypes of motoneuron disease shortly after diagnosis suggests that these are all part of a single spectrum of multisystem neurodegenerative disease. Voxel-based analysis was more sensitive to detect longitudinal changes than diffusion tensor tractography of the corticospinal tract. Voxel-based analyses may be particularly valuable in the evaluation of motor and extra-motor white matter involvement in the early symptomatic stages of motoneuron disease, and for monitoring the spread of pathology over time.

Background: The success of antihypertensive drugs may be improved by better prediction of their efficacy in individual patients. The objective of our study was to determine whether genetic variation predicts the individual systolic blood pressure (SBP) response to antihypertensive drugs and to assess to what extent the individual treatment response could be explained by the combined effects of known demographic, environmental, and genetic factors., Methods: A population-based, crossover, open-label randomized treatment study stratified for ethnicity in 102 mildly hypertensive patients aged 35-60 years in an outpatient hypertension clinic (the ROTATE study). Patients underwent five successive 6-week treatment episodes of single-drug treatment in a randomized order with representatives of the major antihypertensive drug classes. The primary outcome measure was the DeltaSBP after 6-week drug therapy., Results: Participants (n = 97) completed 407 treatment episodes. The estimated unpredictable natural variation of SBP within individuals was 65% of the total study variance. The primary analysis model that considered the effects of environmental, demographic, and genetic factors and their interactions to SBP response to antihypertensive drugs, explained 23% of the total variance accounting for 66% of the predictable variance. Ethnicity, low sodium intake, and ADD1 614G-->T polymorphism were the only drug-related predictors. A number of genetic variants (ADD1 614G-->T, ADRB1 145A-->G, ADRB2 79C-->G, CYP11B2 -344C-->T, and SLC12A3 78G-->A) contributed significantly (9%) to the total variance of the SBP response. The contribution of each individual single-nucleotide polymorphism (SNP) ranged from 1.1 to 2.4%., Conclusions: Genetic factors are relevant and independent determinants of antihypertensive drug effects in a multiracial population.

Motivation: Canonical correlation analysis (CCA) can be used to capture the underlying genetic background of a complex disease, by associating two datasets containing information about a patient's phenotypical and genetic details. Often the genetic information is measured on a qualitative scale, consequently ordinary CCA cannot be applied to such data. Moreover, the size of the data in genetic studies can be enormous, thereby making the results difficult to interpret., Results: We developed a penalized non-linear CCA approach that can deal with qualitative data by transforming each qualitative variable into a continuous variable through optimal scaling. Additionally, sparse results were obtained by adapting soft-thresholding to this non-linear version of the CCA. By means of simulation studies, we show that our method is capable of extracting relevant variables out of high-dimensional sets. We applied our method to a genetic dataset containing 144 patients with glial cancer., Contact: s.waaijenborg@amc.uva.nl.

Knowledge on the aetiology of vasovagal syncope (VVS) is of great importance to optimize its diagnostic and therapeutic options. To unravel the largely unknown pathophysiology, studies on genetic aspects of VVS can be of use. This systematic review on all available literature aims to provide an overview of the current knowledge of VVS genetics. The MEDLINE and EMBASE database were systematically searched for all studies discussing genetic factors as a cause of VVS. Hereditary aspects of VVS were studied in 19 studies. Six studies determined a positive family history in, respectively, 19-90% of the VVS patients. These numbers, however, are not higher than the cumulative incidence of VVS in the general population (35-39%). Four studies examined potential genetic polymorphisms associated with VVS. Only a Gly389 allele was more frequently present in VVS patients with a positive HUT test, although the significance level was set much higher than usual in genetic studies, and this result has not been replicated so far. Knowledge on genetic aspects of VVS could be very useful in clinical practice and research, but the current evidence that it has a genetic basis is not very strong.

Introduction: Lifelong premature ejaculation (LPE) is characterized by persistent intravaginal ejaculation latency times (IELTs) of less than 1 minute, and has been postulated as a neurobiological dysfunction with genetic vulnerability for the short IELTs, related to disturbances of central serotonin (5-hydroxytryptamine [5-HT]) neurotransmission and 5-HT receptor functioning., Aim: To investigate the relationship between 5-HT transporter gene-linked polymorphism (5-HTTLPR) and short IELTs in men with lifelong PE., Methods: A prospective study was conducted in 89 Dutch Caucasian men with lifelong PE. IELT during coitus was assessed by stopwatch over a 1-month period. Controls consisted of 92 Dutch Caucasian men. All men with LPE were genotyped for a 5-HTT-promoter polymorphism. Allele frequencies and genotypes of short (S) and long (L) variants of 5-HTTLPR polymorphism were compared between patients and controls. Association between LL, SL, and SS genotypes, and the natural logarithm of the IELT in men with LPE was investigated., Main Outcome Measures: IELT measured by stopwatch, 5-HTTLPR polymorphism., Results: In men with lifelong PE, the geometric mean, median, and natural mean IELTs were 21, 26, and 32 seconds, respectively. There were no significant differences in the 5-HTT polymorphism alleles and genotypes between 89 Dutch Caucasian men with LPE (S 47%, L 53%/LL 29%, SL 48%, SS 22%) and 92 Dutch Caucasian controls (S 48%, L 52%/LL 29%, SL 45%, SS 26%). In men with lifelong PE there was a statistically significant difference between LL, SL, and SS genotypes in their geometric mean IELT (P < or = 0.027); the LL genotypes had significantly shorter IELTs than the SS and SL genotypes., Conclusions: The 5-HTTLPR polymorphism is associated with significant effects on the latency to ejaculate in men with lifelong PE. Men with SS and SL genotypes have 100% and 90% longer ejaculation time, respectively than men with LL genotypes.

Aims: Inhibition of cholesteryl ester transfer protein (CETP) increases HDL-cholesterol. However, its combination with statins may increase mortality by factors incompletely understood. We previously observed that patients with intrinsically low CETP levels (carriers of the TaqIB-B2 allele) may have less benefit from statin therapy, and here tested this pharmacogenetic hypothesis on long-term outcomes., Methods and Results: We performed a 10-year follow-up analysis in 812 coronary artery disease (CAD) patients (REGRESS cohort), treated with statins after an initial 2-year study period. Carriers of TaqIB-B2 showed reduced CETP levels and higher HDL-cholesterol (P < 0.001 for both). Despite these lower CETP and higher HDL-cholesterol levels, hazard ratios per B2 copy were 1.59 (P = 0.01) for atherosclerotic disease death, 1.53 (P = 0.03) for ischaemic heart disease death, and 1.30 (P = 0.04) for all-cause mortality. Haplotype-effects analysis provided even stronger basis for the genetics involved: one risk-haplotype was identified that was highly significantly associated with these endpoints., Conclusion: In statin-treated male CAD patients, genetic variation conferring low CETP levels is associated with increased 10-year mortality. This suggests that efficacy of statin therapy to reduce cardiovascular risk depends on CETP genotype and associated CETP plasma levels. This effect may need consideration when administering CETP inhibition to CAD patients.

We propose random-effects models to summarize and quantify the accuracy of the diagnosis of multiple lesions on a single image without assuming independence between lesions. The number of false-positive lesions was assumed to be distributed as a Poisson mixture, and the proportion of true-positive lesions was assumed to be distributed as a binomial mixture. We considered univariate and bivariate, both parametric and nonparametric mixture models. We applied our tools to simulated data and data of a study assessing diagnostic accuracy of virtual colonography with computed tomography in 200 patients suspected of having one or more polyps.

Objective: To investigate the utility of serum COMP level measurements as a predictor of future damage of the weight-bearing (large) joints in RA patients participating in intensive exercise., Methods: Data of the 281 completers of a 2-yr randomized controlled trial (Rheumatoid Arthritis Patients In Training; RAPIT) comparing the effects of usual care physical therapy with high-intensity weight-bearing exercises were analysed. The primary outcome variable was defined as the change in radiological joint damage (Larsen score) of the large joints. Potential predictors of outcome were defined: baseline and change in serum level of COMP after 3 months, baseline radiological damage of the large and small joints, number of months on glucocorticoids, change in disease activity and in physical capacity (aerobic fitness and muscle strength) after 2 yrs, and participation in the exercise group., Results: In cross-sectional evaluation of baseline data, we found strong association between the high serum COMP level and current damage of the large joints. Serum COMP level at baseline, however, was not associated with an increased rate of radiological joint damage after 2 yrs of follow-up. Furthermore, neither interaction between baseline COMP level and participation in exercises, nor change in COMP level after 3 months of exercising were associated with future damage of the large joints., Conclusion: Neither baseline serum COMP level nor its individual change after 3 months from start of intensive exercise predict longitudinal progression of damage of the large joints in this population.

Background: Optimal cutoff values for tests results involving continuous variables are often derived in a data-driven way. This approach, however, may lead to overly optimistic measures of diagnostic accuracy. We evaluated the magnitude of the bias in sensitivity and specificity associated with data-driven selection of cutoff values and examined potential solutions to reduce this bias., Methods: Different sample sizes, distributions, and prevalences were used in a simulation study. We compared data-driven estimates of accuracy based on the Youden index with the true values and calculated the median bias. Three alternative approaches (assuming a specific distribution, leave-one-out, smoothed ROC curve) were examined for their ability to reduce this bias., Results: The magnitude of bias caused by data-driven optimization of cutoff values was inversely related to sample size. If the true values for sensitivity and specificity are both 84%, the estimates in studies with a sample size of 40 will be approximately 90%. If the sample size increases to 200, the estimates will be 86%. The distribution of the test results had little impact on the amount of bias when sample size was held constant. More robust methods of optimizing cutoff values were less prone to bias, but the performance deteriorated if the underlying assumptions were not met., Conclusions: Data-driven selection of the optimal cutoff value can lead to overly optimistic estimates of sensitivity and specificity, especially in small studies. Alternative methods can reduce this bias, but finding robust estimates for cutoff values and accuracy requires considerable sample sizes.

Introduction: The intravaginal ejaculation latency time (IELT) behaves in a skewed manner and needs the appropriate statistics for correct interpretation of treatment results., Aims: To explain the rightful use of geometrical mean IELT values and the fold increase of the geometric mean IELT because of the positively skewed IELT distribution., Methods: Linking theoretical arguments to the outcome of several selective serotonin reuptake inhibitor and modern antidepressant study results., Main Outcome Measures: Geometric mean IELT and fold increase of geometrical mean IELT., Results: Log-transforming each separate IELT measurement of each individual man is the basis for the calculation of the geometric mean IELT. A drug-induced positively skewed IELT distribution necessitates the calculation of the geometric mean IELTs at baseline and during drug treatment. In a positively skewed IELT distribution, the use of the "arithmetic" mean IELT risks an overestimation of the drug-induced ejaculation delay as the mean IELT is always higher than the geometric mean IELT. Strong ejaculation-delaying drugs give rise to a strong positively skewed IELT distribution, whereas weak ejaculation-delaying drugs give rise to (much) less skewed IELT distributions. Ejaculation delay is expressed in fold increase of the geometric mean IELT., Conclusions: Drug-induced ejaculatory performance discloses a positively skewed IELT distribution, requiring the use of the geometric mean IELT and the fold increase of the geometric mean IELT.

Introduction: Whether men with lifelong premature ejaculation (PE) prefer on-demand drug treatment to delay ejaculation time to daily drug treatment, has never been studied as a separate study question., Aim: To study how men with lifelong PE feel about the use of serotonergic antidepressants, and which option they would prefer for themselves: either a daily drug, a drug to be used on demand, or a topical anesthetic cream to be applied on demand., Main Outcome Measures: Treatment preference was determined by questionnaire., Methods: An observational questionnaire survey in a clinical sample. Preferences of different treatment strategies were queried before and after standard efficacy and safety information., Results: A consecutive group of 88 men with lifelong PE who decided for themselves to be seen for rapid ejaculation was studied. The age was 37 +/- 11 years (mean +/- SD), range 18-64 years. None of these men was ever treated for PE and 21% used medication that did not affect sexual performance. Of them, 71 (81%) preferred a drug for daily use, 14 (16%) a drug on demand, while three men preferred topical anesthetic cream. Those men who initially preferred daily treatment did not change their view after standard information about efficacy and side effects, while 9 of 17 men who initially preferred on-demand drug treatment had switched their preferences to daily oral drug usage. Around 60% of men did not care about the nature of the drug, i.e., an antidepressant. The most frequently reported argument to prefer daily drug treatment was that this strategy would have the least effects toward the spontaneity of having sex., Conclusion: As opposed to agents that must be taken 4-6 hours prior to coitus and with the methods used here, this group of Dutch men with lifelong PE favor uninterrupted daily drug treatment to delay ejaculation mainly because daily treatment guarantees no interference with the spontaneity of having sex.

Aims: To investigate the influence of different LDL-receptor (LDLR) gene mutations on age at first cardiovascular event in familial hypercholesterolaemia (FH) patients., Methods and Results: Dutch FH patients (n = 862) with known LDLR mutations from a retrospective cohort study were included. A gamma frailty Cox model was used. An event was defined as the first cardiovascular event. Gender, hypertension, smoking, diabetes, HDL cholesterol, LDL cholesterol (LDL-C), or triglycerides were included as covariates. Furthermore, the effect of LDLR mutation type on LDL and HDL cholesterol levels was investigated using mixed effects models, including gender, smoking, body mass index, and age at time of lipid measurement as covariates. A total of 86 different LDLR mutations were present in this cohort. Twenty-two percent of patients experienced an event (median age: 47.1 year; range: 25.6-85.8 years). The effect of LDLR mutation type on event-free survival is only significant in the models without LDL-C levels. Also, LDLR mutation type was significantly associated with LDL-C levels (P = 0.007), but not with HDL cholesterol levels (P = 0.12)., Conclusion: In the present study, LDL-C levels are a more important risk factor of event-free survival than the type of LDLR mutation.