[Show abstract][Hide abstract] ABSTRACT: Recently, we demonstrated that losartan reduced the aortic root dilatation rate (AoDR) in adults with Marfan syndrome (MFS); however, responsiveness was diverse. The aim was to determine the role of transforming growth factor-β (TGF-β) as therapeutic biomarker for effectiveness of losartan on AoDR.
[Show abstract][Hide abstract] ABSTRACT: In prognostic studies, the lasso technique is attractive since it improves the quality of predictions by shrinking regression coefficients, compared to predictions based on a model fitted via unpenalized maximum likelihood. Since some coefficients are set to zero, parsimony is achieved as well. It is unclear whether the performance of a model fitted using the lasso still shows some optimism. Bootstrap methods have been advocated to quantify optimism and generalize model performance to new subjects. It is unclear how resampling should be performed in the presence of multiply imputed data.
BMC Medical Research Methodology 10/2014; 14(1):116. · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This paper presents an extension of the joint modeling strategy for the case of multiple longitudinal outcomes and repeated infections of different types over time, motivated by postkidney transplantation data. Our model comprises two parts linked by shared latent terms. On the one hand is a multivariate mixed linear model with random effects, where a low-rank thin-plate spline function is incorporated to collect the nonlinear behavior of the different profiles over time. On the other hand is an infection-specific Cox model, where the dependence between different types of infections and the related times of infection is through a random effect associated with each infection type to catch the within dependence and a shared frailty parameter to capture the dependence between infection types. We implemented the parameterization used in joint models which uses the fitted longitudinal measurements as time-dependent covariates in a relative risk model. Our proposed model was implemented in OpenBUGS using the MCMC approach.
[Show abstract][Hide abstract] ABSTRACT: Infections occur in 30% of stroke patients and are associated with unfavorable outcomes. Preventive antibiotic therapy lowers the infection rate after stroke, but the effect of preventive antibiotic treatment on functional outcome in patients with stroke is unknown. The PASS is a multicenter, prospective, phase three, randomized, open-label, blinded end-point (PROBE) trial of preventive antibiotic therapy in acute stroke. Patients are randomly assigned to either ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to standard stroke-unit care, or standard stroke-unit care without preventive antibiotic therapy. The aim of this study is to assess whether preventive antibiotic treatment improves functional outcome at 3 months by preventing infections. This paper presents in detail the statistical analysis plan (SAP) of the Preventive Antibiotics in Stroke Study (PASS) and was submitted while the investigators were still blinded for all outcomes.
[Show abstract][Hide abstract] ABSTRACT: Background: Patients who visit their General Practitioner (GP) very frequently over extended periods of time often have multimorbidity and are costly in primary and specialist healthcare. We investigated the impact of patient-level psychosocial and GP-level factors on the persistence of frequent attendance (FA) in primary care. Methods: Two-year prospective cohort study in 623 incident adult frequent attenders (N90th attendance centile; age and sex-adjusted) in 2009. Information was collected through questionnaires (patients, GPs) and GPs' patient data. We used multilevel, ordinal logistic regression analysis, controlling for somatic illness and demographic fac-tors with FA in 2010 and/or 2011 as the outcome. Results: Other anxiety (odds ratio (OR) 2.00; 95% confidence interval from 1.29 to 3.10) over 3 years and the number of life events in 3 years (OR 1.06; 1.01–1.10 per event; range of 0 to 12) and, at baseline, panic disorder (OR 5.40; 1.67–17.48), other anxiety (OR 2.78; 1.04–7.46), illness behavior (OR 1.13; 1.05–1.20 per point; 28-point scale) and lack of mastery (OR 1.08; 1.01–1.15 per point; 28-point scale) were associated with persistence of FA. We found no evidence of synergistic effects of somatic, psychological and social problems. We found no strong evidence of effects of GP characteristics. Conclusion: Panic disorder, other anxiety, negative life events, illness behavior and lack of mastery are indepen-dently associated with persistence of frequent attendance. Effective intervention at these factors, apart from their intrinsic benefits to these patients, may reduce attendance rates, and healthcare expenditures in primary and specialist care.
Journal of Psychosomatic Research 08/2014; j.jpsychores.2014.08.003.. · 3.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 2. The history of diagnosing Marfan syndrome 3. The FBN1 gene 4. Overview of literature 5. Different types of FBN1 mutations 6. Conclusion 7. Expert opinion Introduction: Marfan syndrome (MFS) is a connective tissue disorder with highly variable features in cardiovascular, ocular and skeletal systems. MFS is generally caused by one of the 2900-plus described different genetic mutations in the fibrillin-1 gene (FBN1). Areas covered: By revising the Ghent criteria in 2010, more weight has been given to genetic testing in the diagnosis of MFS. We provide an overview of correlations between different mutation types and clinical MFS features by using the Universal Mutation Database (UMD). Expert opinion: In this paper, we classified FBN1 mutations based on their action on DNA level and we found the following genotype--phenotype corre-lations: i) cysteine mutations are associated with ectopia lentis; ii) introduc-tion of a cysteine leads to less severe involvement of cardiovascular and skeletal system; iii) whole gene deletions and premature termination codon (PTC) mutations are associated with increased skeletal and cardiovascular involvement, but lower prevalence of ectopia lentis and iv) intronic mutations lead to MFS by exon skipping, small insertions/deletions and PTC mutations. Classification based on mutation effect at protein level (reduced vs truncated/deformed fibrillin-1) may partly explain genotype--phenotype asso-ciation and warrants further investigation for individualized prognosis and treatment.
[Show abstract][Hide abstract] ABSTRACT: Carotid intima-media thickness (CIMT) is a marker for atherosclerosis. Adult post-coarctectomy patients (CoA) demonstrate an increased cardiovascular risk and increased CIMT compared to controls. This study evaluates the effect of high dose statins on the change in CIMT and cardiovascular risk.
International Journal of Cardiology 06/2014; · 6.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In population-based observational studies, non-participation and delayed response to the invitation toparticipate are complications that often arise during the recruitment of a sample. When both are notproperly dealt with, the composition of the sample can be different from the desired composition.Inviting too many individuals or too few individuals from a particular subgroup could lead tounnecessary costs or decreased precision. Another problem is that there is frequently no or onlypartial information available about the willingness to participate. In this situation, we cannot adjustthe recruitment procedure for non-participation before the recruitment period starts.
BMC Medical Research Methodology 06/2014; 14(1):81. · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality worldwide. Increasing age has been associated with elevated circulating levels of pro-inflammatory mediators. We aimed to determine the impact of aging on the systemic inflammatory response to CAP. In total 201 CAP patients were enrolled. Blood samples were obtained upon presentation, and day 2, 3, 5. For the current analysis patients ≤ 50 and ≥ 80 years were included. Pneumonia Severity Index (PSI) score was calculated at presentation. The study encompassed 46 CAP patients ≤ 50 years (median 37 years) and 41 CAP patients ≥ 80 years (median 84 years). In both groups Streptococcus pneumoniae was the common causative microorganism. Whereas most young patients had a PSI score of I (54%), 98% of old patients had a PSI score ≥ III (p < 0.001). Four elderly patients died versus none of the young patients (p = 0.045). Old patients demonstrated lower serum C-reactive protein levels on admission and during the course of their hospitalization (p = 0.001) in spite of more severe disease. Serum concentrations of pro-inflammatory (interleukin (IL)-6 and IL-8) and anti-inflammatory cytokines (IL-10 and IL-1 receptor antagonist) did not differ between age groups, although admission IL-8 levels tended to be higher in old patients (p = 0.05). Cytokine levels positively correlated with PSI in young but not in old patients. These results suggest that elderly patients show an absolute (C-reactive protein) or relative (cytokines) reduction in their systemic inflammatory response on admission for CAP.
Clinical Microbiology and Infection 06/2014; · 4.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P<1 × 10(-4)). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an 'extreme genetics' approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power.European Journal of Human Genetics advance online publication, 11 June 2014; doi:10.1038/ejhg.2014.101.
European journal of human genetics: EJHG 06/2014; · 3.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study is to explore DNA hypermethylation analysis in sputum and exhaled breath analysis for their complementary, non-invasive diagnostic capacity in lung cancer.
Journal of clinical pathology. 06/2014; 67(8):707-711.
[Show abstract][Hide abstract] ABSTRACT: -The pathogenic phospholamban (PLN) R14del mutation causes dilated and/or arrhythmogenic right ventricular cardiomyopathies and is associated with an increased risk of malignant ventricular arrhythmias and end-stage heart failure. We performed a multicentre study to evaluate mortality, cardiac disease outcome, and risk factors for malignant ventricular arrhythmias in a cohort of PLN R14del mutation carriers.
[Show abstract][Hide abstract] ABSTRACT: Asthma and atopy share common characteristics including type 2 helper T-cell mediated inflammation. However, only asthma is associated with variable airways obstruction. The complex cellular and molecular pathways distinguishing asthma and atopy can now be captured by transcriptomic analysis (RNA-Seq). We hypothesized that the transcriptomic profile of airway smooth muscle (ASM) distinguishes atopic asthma from atopic healthy controls. First, we compared the ASM transcriptomic profiles of endobronchial biopsies between glucocorticoid-free, atopic asthma patients, and atopic and non-atopic healthy controls. Second, we investigated the association between ASM transcriptomic profiles and airway function.
[Show abstract][Hide abstract] ABSTRACT: To evaluate differences in functional parameters and reproducibility between short axis and axial slice orientation in the quantitative evaluation of the systemic right ventricle by cardiovascular magnetic resonance.
Cross-sectional evaluation comparing two methods (Bland-Altman).
Tertiary care outpatients.
Quantitative cardiovascular magnetic resonance evaluation using short axis or axial slice orientation.
Intraobserver variance, interobserver variance and systematic differences in systemic right ventricular volumes, ejection fraction, and mass between both methods.
Twenty-two patients (mean age 33 ± 7 years) with systemic right ventricle (three with congenitally corrected transposition of the great arteries and 19 with atrially switched transposition of the great arteries).
Compared with short axis slices, analysis of axial slices resulted in higher end systolic volume (6.6%, P < .01), while mass (-10.8%, P < .01) and ejection fraction (-8.9%, P < .01) turned out lower. Intraobserver and interobserver reproducibility were similar for both methods when measuring end-diastolic and end-systolic volumes. However, ejection fraction and stroke volume were measured more consistently in axial orientation, while ventricular mass was measured more consistently in short axis orientation.
There are significant differences in volume, mass, and function between measurements in axial and short axis orientation. Ejection fraction and stroke volume, which have a high clinical relevance, were measured more consistently in axial slice orientation. Consequently, we recommend using axial slice orientation in patients with a systemic right ventricle.
[Show abstract][Hide abstract] ABSTRACT: There is a need for biological markers of the acute respiratory distress syndrome (ARDS). Exhaled breath contains hundreds of metabolites in the gas phase, some of which reflect (patho)physiological processes. We aimed to determine the diagnostic accuracy of metabolites in exhaled breath as biomarkers of ARDS.Breath from ventilated intensive care unit patients (n = 101) was analysed using gas chromatography and mass spectrometry during the first day of admission. ARDS was defined by the Berlin definition. Training and temporal validation cohorts were used.23 patients in the training cohort (n = 53) had ARDS. Three breath metabolites, octane, acetaldehyde and 3-methylheptane, could discriminate between ARDS and controls with an area under the receiver operating characteristic curve (AUC) of 0.80. Temporal external validation (19 ARDS cases in a cohort of 48) resulted in an AUC of 0.78. Discrimination was insensitive to adjustment for severity of disease, a direct or indirect cause of ARDS, comorbidities, or ventilator settings. Combination with the lung injury prediction score increased the AUC to 0.91 and improved net reclassification by 1.17.Exhaled breath analysis showed good diagnostic accuracy for ARDS, which was externally validated. These data suggest that exhaled breath analysis could be used for the diagnostic assessment of ARDS.
European Respiratory Journal 04/2014; · 6.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Doel Onderzoeken in hoeverre patiëntgegevens en huisartskenmerken de zorgkosten verklaren van patiënten die hun huisarts
frequent bezoeken gedurende 1-3 jaar.
Opzet Observationeel onderzoek.
Methode Er werd gebruikgemaakt van huisartsregistratiebestanden en declaratiegegevens van een zorgverzekeraar. Gepseudonimiseerde
gegevens uit de dossiers van 16.531 patiënten (39 huisartsen) werden gekoppeld aan eerste- en tweedelijns
kosten vergoed door een zorgverzekeraar in de periode 2007-2009. Huisartskenmerken werden verzameld
via administratieve gegevens en een vragenlijst. Via multilevel lineaire regressieanalyse schatten we het effect
van de duur van het frequente bezoek op de zorgkosten, na correctie voor aandoeningen van de patiënt en huisartskenmerken.
Resultaten De ongecorrigeerde gemiddelde uitgaven in 3 jaar waren voor niet-frequente bezoekers €5.044 en voor frequente
bezoekers €15.824. Na correctie voor bekende confounders bleven de zorgkosten voor frequente bezoekers aanzienlijk
hoger. Hoe langer het frequente bezoek bestond, hoe hoger de kosten waren. Vergeleken met niet-frequente
bezoekers waren de gecorrigeerde kosten voor 3 jaar zorg €1723 hoger voor patiënten die gedurende 1 jaar
frequente bezoeker waren, en €5293 hoger voor patiënten die 3 jaar lang frequent bezoeker waren.
Conclusie Frequente bezoekers van de huisarts genereren hoge zorgkosten, zowel in de eerste als in de tweede lijn. Deze kosten
kunnen deels worden verklaard door de aandoeningen van patiënten en door kenmerken en werkstijl van de huisarts.
Mogelijk spelen aandoeningen die nu niet door de huisarts worden geregistreerd, een rol. De mechanismen
die deze extra uitgaven veroorzaken vereisen nader onderzoek.
Nederlands tijdschrift voor geneeskunde 03/2014; 2014;158: A7117(158):A7117.
[Show abstract][Hide abstract] ABSTRACT: Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.
The American Journal of Human Genetics 02/2014; · 11.20 Impact Factor