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Showing papers by "Diederick E. Grobbee published in 2011"


Journal ArticleDOI
TL;DR: Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.

2,123 citations


Journal ArticleDOI
Georg Ehret1, Georg Ehret2, Georg Ehret3, Patricia B. Munroe4  +388 moreInstitutions (110)
06 Oct 2011-Nature
TL;DR: A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function, and these findings suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Abstract: Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

1,829 citations


Journal ArticleDOI
TL;DR: Preventive factors should not be used to calculate measures of interaction on an additive scale without recoding, and recoding of preventive factors should be done such that the stratum with the lowest risk becomes the reference category when both factors are considered jointly.
Abstract: Measures of interaction on an additive scale (relative excess risk due to interaction [RERI], attributable proportion [AP], synergy index [S]), were developed for risk factors rather than preventive factors. It has been suggested that preventive factors should be recoded to risk factors before calculating these measures. We aimed to show that these measures are problematic with preventive factors prior to recoding, and to clarify the recoding method to be used to circumvent these problems. Recoding of preventive factors should be done such that the stratum with the lowest risk becomes the reference category when both factors are considered jointly (rather than one at a time). We used data from a case-control study on the interaction between ACE inhibitors and the ACE gene on incident diabetes. Use of ACE inhibitors was a preventive factor and DD ACE genotype was a risk factor. Before recoding, the RERI, AP and S showed inconsistent results (RERI = 0.26 [95%CI: −0.30; 0.82], AP = 0.30 [95%CI: −0.28; 0.88], S = 0.35 [95%CI: 0.02; 7.38]), with the first two measures suggesting positive interaction and the third negative interaction. After recoding the use of ACE inhibitors, they showed consistent results (RERI = −0.37 [95%CI: −1.23; 0.49], AP = −0.29 [95%CI: −0.98; 0.40], S = 0.43 [95%CI: 0.07; 2.60]), all indicating negative interaction. Preventive factors should not be used to calculate measures of interaction on an additive scale without recoding.

432 citations


Journal ArticleDOI
TL;DR: In this paper, the authors conducted a meta-analysis of observational studies relating metabolic syndrome to determinants of testosterone status [total testosterone (TT), free testosterone (FT) and sex hormone binding globulin (SHBG).
Abstract: BACKGROUND Accumulating evidence suggests a sex-dependent role of circulating testosterone in the metabolic syndrome (MetS). METHODS We conducted a meta-analysis of observational studies (PubMed and EMBASE-1 May 2010) relating MetS to determinants of testosterone status [total testosterone (TT), free testosterone (FT) and sex hormone-binding globulin (SHBG)]. RESULTS A total of 52 studies were identified, comprising 22 043 men and 7839 women and presenting relative risk (RR) estimates or hormone levels for subjects with and without MetS. Endogenous TT and FT levels were lower in men with MetS [TT mean difference = -2.64 nmol/l, 95% confidence interval (CI) -2.95 to -2.32; FT standardized mean difference = -0.26 pmol/l, 95% CI -0.39 to -0.13] and higher in women with MetS (TT mean difference = 0.14 nmol/l, 95% CI 0.07-0.20; FT standardized mean difference = 0.52 pmol/l, 95% CI 0.33-0.71) compared with those without. Similarly, men with higher TT levels had a lower MetS risk (RR estimate = 0.38, 95% CI 0.28-0.50) whereas higher TT levels increased the risk of MetS in women (RR estimate = 1.68, 95% CI 1.15-2.45). In both sexes, higher SHBG levels were associated with a reduced risk (men: RR estimate = 0.29, 95% CI 0.21-0.41; women: RR estimate = 0.30, 95% CI 0.21-0.42). CONCLUSION This meta-analysis supports the presence of a sex-dependent association between testosterone and MetS: TT and FT levels are lower in men with MetS, whereas they are higher in women with MetS. There are no indications for a sex-specific association between SHBG and MetS. In both men and women, MetS is associated with lower SHBG levels.

276 citations


Journal ArticleDOI
Gunter Schumann1, Lachlan J. M. Coin2, Anbarasu Lourdusamy1, Pimphen Charoen3, Pimphen Charoen4, Karen H. Berger5, David Stacey1, Sylvane Desrivières1, Fazil Aliev6, Anokhi Ali Khan2, Najaf Amin7, Yurii S. Aulchenko7, Georgy Bakalkin8, Stephan J. L. Bakker9, Beverley Balkau10, Beverley Balkau11, Joline W.J. Beulens12, Ainhoa Bilbao, Rudolf A. de Boer9, Delphine Beury13, Michiel L. Bots12, Elemi J. Breetvelt12, Stéphane Cauchi13, Christine Cavalcanti-Proença13, John C. Chambers2, Toni-Kim Clarke1, Norbert Dahmen14, Eco J. C. de Geus15, Danielle M. Dick6, Francesca Ducci1, Alanna C. Easton1, Howard J. Edenberg15, Tõnu Esko16, Alberto Fernández-Medarde17, Tatiana Foroud15, Nelson B. Freimer18, Jean-Antoine Girault19, Diederick E. Grobbee, Simonetta Guarrera, Daniel F. Gudbjartsson20, Anna-Liisa Hartikainen21, Andrew C. Heath22, Victor Hesselbrock23, Albert Hofman7, Jouke-Jan Hottenga24, Matti Isohanni21, Jaakko Kaprio25, Kay-Tee Khaw26, Brigitte Kuehnel, Jaana Laitinen, Stéphane Lobbens13, Jian'an Luan26, Massimo Mangino27, Matthieu Maroteaux19, Giuseppe Matullo28, Mark I. McCarthy29, Christian Mueller30, Christian Mueller1, Gerjan Navis9, Mattijs E. Numans12, Alejandro Núñez17, Dale R. Nyholt31, Charlotte Onland-Moret9, Charlotte Onland-Moret12, Ben A. Oostra8, Paul F. O'Reilly2, Miklós Palkovits32, Brenda W.J.H. Penninx24, Brenda W.J.H. Penninx33, Silvia Polidoro, Anneli Pouta, Inga Prokopenko29, Fulvio Ricceri, Eugenio Santos17, Johannes H. Smit24, Nicole Soranzo34, Nicole Soranzo1, Kijoung Song35, Ulla Sovio2, Michael Stumvoll36, Ida Surakk, Thorgeir E. Thorgeirsson20, Unnur Thorsteinsdottir20, Claire Troakes1, Thorarinn Tyrfingsson, Anke Tönjes36, Cuno S.P.M. Uiterwaal12, André G. Uitterlinden7, Pim van der Harst9, Yvonne T. van der Schouw12, Oliver Staehlin, Nicole Vogelzangs24, Peter Vollenweider37, Gérard Waeber37, Nicholas J. Wareham26, Dawn M. Waterworth35, John Whitfield31, Erich Wichmann38, Gonneke Willemsen24, Jacqueline C.M. Witteman7, Xin Yuan35, Guangju Zhai1, Jing Hua Zhao26, Weihua Zhang2, Nicholas G. Martin31, Andres Metspalu16, Angela Doering, James Scott2, Tim D. Spector1, Ruth J. F. Loos26, Dorret I. Boomsma24, Vincent Mooser35, Leena Peltonen25, Leena Peltonen34, Kari Stefansson20, Cornelia M. van Duijn7, Paolo Vineis, Wolfgang H. Sommer, Jaspal S. Kooner2, Rainer Spanagel, Ulrike Heberlein5, Marjo-Riitta Järvelin21, Paul Elliott2 
TL;DR: A genome-wide association study meta-analysis of ∼2.5 million directly genotyped or imputed SNPs with alcohol consumption among 12 population-based samples of European ancestry finds a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples and finds a regulator of alcohol consumption.
Abstract: Alcohol consumption is a moderately heritable trait, but the genetic basis in humans is largely unknown, despite its clinical and societal importance. We report a genome-wide association study meta-analysis of similar to 2.5 million directly genotyped or imputed SNPs with alcohol consumption (gram per day per kilogram body weight) among 12 population-based samples of European ancestry, comprising 26,316 individuals, with replication genotyping in an additional 21,185 individuals. SNP rs6943555 in autism susceptibility candidate 2 gene (AUTS2) was associated with alcohol consumption at genome-wide significance (P = 4 x 10(-8) to P = 4 x 10(-9)). We found a genotype-specific expression of AUTS2 in 96 human prefrontal cortex samples (P = 0.026) and significant (P < 0.017) differences in expression of AUTS2 in whole-brain extracts of mice selected for differences in voluntary alcohol consumption. Downregulation of an AUTS2 homolog caused reduced alcohol sensitivity in Drosophila (P < 0.001). Our finding of a regulator of alcohol consumption adds knowledge to our understanding of genetic mechanisms influencing alcohol drinking behavior.

265 citations


Journal ArticleDOI
01 Sep 2011
TL;DR: This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.
Abstract: Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ~2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10; LPA:p<10; 1p13.3:p<10) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ~4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes. © 2011 Butterworth et al.

228 citations


Gunter Schumann, Lachlan J. M. Coin, Anbarasu Lourdusamy, Pimphen Charoen, Karen H. Berger, David Stacey, Sylvane Desrivières, Fazil Aliev, Anokhi Ali Khan, Najaf Amin, Yurii S. Aulchenko, Georgy Bakalkin, Stephan J. L. Bakker, Beverley Balkau, Joline W.J. Beulens, Ainhoa Bilbao, Rudolf A. de Boer, Delphine Beury, Michiel L. Bots, Elemi J. Breetvelt, Stéphane Cauchi, Christine Cavalcanti-Proença, John C. Chambers, Toni-Kim Clarke, Norbert Dahmen, Eco J. C. de Geus, Danielle M. Dick, Francesca Ducci, Alanna C. Easton, Howard J. Edenberg, Tonu Esk, Alberto Fernández-Medarde, Tatiana Foroud, Nelson B. Freimer, Jean-Antoine Girault, Diederick E. Grobbee, Simonetta Guarrera, Daniel F. Gudbjartsson, Anna-Liisa Hartikainen, Andrew Heath, Victor Hesselbrock, Albert Hofman, Jouke-Jan Hottenga, Matti Isohanni, Jaakko Kaprio, Kay-Tee Khaw, Brigitte Kuehnel, Jaana Laitinen, Stéphane Lobbens, Jian'an Luan, Massimo Mangino, Matthieu Maroteaux, Giuseppe Matullo, Mark I. McCarthy, Christian Mueller, Gerjan Navis, Mattijs E. Numans, Alejandro Núñez, Dale R. Nyholt, Charlotte Onland-Moret, Ben A. Oostra, Paul F. O'Reilly, Miklós Palkovits, Brenda W.J.H. Penninx, Silvia Polidoro, Anneli Pouta, Inga Prokopenko, Fulvio Ricceri, Eugenio Santos, Johannes H. Smit, Nicole Soranzo, Kijoung Song, Ulla Sovio, Michael Stumvoll, Ida Surakk, Thorgeir E. Thorgeirsson, Unnur Thorsteinsdottir, Claire Troakes, Thorarinn Tyrfingsson, Anke Toenjes, Cuno S.P.M. Uiterwaal, André G. Uitterlinden, Pim van der Harst, Yvonne T. van der Schouw, Oliver Staehlin, Nicole Vogelzangs, Peter Vollenweider, Gérard Waeber, Nicholas J. Wareham, Dawn M. Waterworth, John Whitfield, Erich Wichmann, Gonneke Willemsen, Jacqueline C.M. Witteman, Xin Yuan, Guangju Zhai, Jing Hua Zhao, Weihua Zhang, Nicholas G. Martin, Andres Metspalu, Angela Doering, James F. Scott, Tim D. Spector, Ruth J. F. Loos, Dorret I. Boomsma, Vincent Mooser, Leena Peltonen, Kari Stefansson, Cornelia M. van Duijn, Paolo Vineis, Wolfgang H. Sommer, Jaspal S. Kooner, Rainer Spanagel, Ulrike Heberlein, Marjo-Riitta Järvelin, Paul Elliott 
01 Jan 2011

225 citations


Journal ArticleDOI
TL;DR: This study confirms the clinical distinction between severe and non‐severe haemophilia A, however, the group of moderate haenophilia patients showed a wide variability, warranting close follow‐up and individualized treatment.
Abstract: The classification of haemophilia originates from 1950s and has been adopted unchallengedly by the ISTH in 2001. The aim of this study was: does the current classification compare onset of bleeding and age at first treatment, as well as annual joint bleeding frequency according to baseline FVIII activity? Data on age and reason of diagnosis, onset of treatment, onset of bleeding and bleeding frequency from 411 patients with haemophilia A born after 1970 were collected. Data were analysed according to base-line FVIII activity levels. Age at diagnosis, onset of bleeding and start of treatment according to FVIII activity were compared with the current classification. Overall, the distinction between severe and non-severe haemophilia was clear. The distinction between mild and moderate haemophilia was more difficult, mostly due to the wide variability in the group of patients with moderate haemophilia. Patients with severe haemophilia experienced their milestones like diagnosis, first treatment and joint bleed earliest, mostly as infants aged 0-3 years, whereas patients with moderate haemophilia reached these milestones around toddler age, 2-7 years, and patients with mild haemophilia reached them when they were in elementary school, around the ages of 5-14 years. This study confirms the clinical distinction between severe and non-severe haemophilia A. However, the group of moderate haemophilia patients showed a wide variability, warranting close follow-up and individualized treatment.

200 citations


Journal ArticleDOI
TL;DR: The quantitative diagnostic contribution of elements of the history and physical examination in the diagnosis of heart failure in primary care outpatients is estimated, which may help to improve clinical decision making.
Abstract: Background—Early diagnosis of nonacute heart failure is crucial because prompt initiation of evidence-based treatment can prevent or slow down further progression. To diagnose new-onset heart failure in primary care is challenging. Methods and Results—This is a cross-sectional diagnostic accuracy study with external validation. Seven hundred twenty-one consecutive patients suspected of new-onset heart failure underwent standardized diagnostic work-up including chest x-ray, spirometry, ECG, N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurement, and echocardiography in specially equipped outpatient diagnostic heart failure clinics. The presence of heart failure was determined by an outcome panel using the initial clinical data and 6-month follow-up data, blinded to biomarker data. Of the 721 patients, 207 (28.7%) had heart failure. The combination of 3 items from history (age, coronary artery disease, and loop diuretic use) plus 6 from physical examination (pulse rate and regularity, displaced a...

194 citations


Journal ArticleDOI
TL;DR: This study has identified a biologically plausible genetic variant associated specifically with AAA, and it is suggested that this variant has a possible functional role in LRP1 expression.
Abstract: Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.

189 citations


Journal ArticleDOI
TL;DR: In this article, a post hoc analysis of 1342 patients with type 2 diabetes mellitus and nephropathy participating in the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan Trial, determined the relationship between month 6 change in SUA and renal endpoints, defined as a doubling of serum creatinine or end-stage renal disease.
Abstract: Emerging data show that increased serum uric acid (SUA) concentration is an independent risk factor for end-stage renal disease. Treatment with the antihypertensive drug losartan lowers SUA. Whether reductions in SUA during losartan therapy are associated with renoprotection is unclear. We therefore tested this hypothesis. In a post hoc analysis of 1342 patients with type 2 diabetes mellitus and nephropathy participating in the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan Trial, we determined the relationship between month 6 change in SUA and renal endpoints, defined as a doubling of serum creatinine or end-stage renal disease. Baseline SUA was 6.7 mg/dL in placebo and losartan-treated subjects. During the first 6 months, losartan lowered SUA by -0.16 mg/dL (95% CI: -0.30 to -0.01; P=0.031) as compared with placebo. The risk of renal events was decreased by 6% (95% CI: 10% to 3%) per 0.5-mg/dL decrement in SUA during the first 6 months. This effect was independent of other risk markers, including estimate glomerular filtration rate and albuminuria. Adjustment of the overall treatment effects for SUA attenuated losartan's renoprotective effect from 22% (95% CI: 6% to 35%) to 17% (95% CI: 1% to 31%), suggesting that approximately one fifth of losartan's renoprotective effect could be attributed to its effect on SUA. Losartan lowers SUA levels compared with placebo treatment in patients with type 2 diabetes mellitus and nephropathy. The degree of reduction in SUA is subsequently associated with the degree in long-term renal risk reduction and explains part of losartan's renoprotective effect. These findings support the view that SUA may be a modifiable risk factor for renal disease.

Journal ArticleDOI
TL;DR: This study investigated the optimal analysing strategy for bleeding data by using the association of residual clotting factor level and number of joint bleeds in moderate and mild patients treated on demand as example, and found Multivariate regression analysis using negative binomial distribution provided the optimum data analytical strategy.
Abstract: Many studies in the field of haemophilia and other coagulation deficiencies require analyses of bleeding frequencies. In haemophilia, the association of bleeding frequency with factor VIII (FVIII) activity levels is known from experience, but significant results are lacking. Bleeding frequencies in haemophilia are highly skewed count data, with large proportions of zeros. Both the skewness and the high amount of zeros pose a problem for standard (linear) modelling techniques. This study investigated the optimal analysing strategy for bleeding data by using the association of residual clotting factor level and number of joint bleeds in moderate and mild patients treated on demand as example. In total, 433 patients with moderate (27%) and mild (73%) haemophilia A treated on demand were included in this study. One year of self-reported data on joint bleed frequency and baseline clotting factor activity were analysed using Poisson, negative binomial, zero-inflated Poisson, and zero-inflated negative binomial distributions. Multivariate regression analysis using negative binomial distribution provided the optimum data analytical strategy. This model showed 18% reduction [Rate ratio (RR) 0.82; 95%confidence interval (CI) 0.77-0.86] of bleeding frequency with every IU dL(-1) increase in residual FVIII activity. The actual association is expected to be higher because of exclusion (30 out of 463 patients) of patients on prophylaxis (baseline FVIII levels 0.01-0.06 IU mL(-1)). The best way to analyse low frequency bleeding data is using a negative binomial distribution.

Journal ArticleDOI
TL;DR: Major cardiovascular events in contemporary populations with type 2 diabetes can be predicted on the basis of routinely measured clinical and biological variables and can be used to quantify risk and guide the intensity of treatment in people with diabetes.
Abstract: Background: Existing cardiovascular risk prediction equations perform non-optimally in different populations with diabetes. Thus, there is a continuing need to develop new equations that will reliably estimate cardiovascular disease (CVD) risk and offer flexibility for adaptation in various settings. This report presents a contemporary model for predicting cardiovascular risk in people with type 2 diabetes mellitus.Design and methods: A 4.5-year follow-up of the Action in Diabetes and Vascular disease: preterax and diamicron-MR controlled evaluation (ADVANCE) cohort was used to estimate coefficients for significant predictors of CVD using Cox models. Similar Cox models were used to fit the 4-year risk of CVD in 7168 participants without previous CVD. The model’s applicability was tested on the same sample and another dataset.Results: A total of 473 major cardiovascular events were recorded during follow-up. Age at diagnosis, known duration of diabetes, sex, pulse pressure, treated hypertension, atrial fib...

Journal ArticleDOI
TL;DR: This article focuses on an invalid method to assess effect modification, which is often used in articles in health sciences journals, namely concluding that there is no effect modification if the confidence intervals of the subgroups are overlapping.
Abstract: In randomized controlled trials as well as in observational studies, researchers are often interested in effects of treatment or exposure in different subgroups, i.e. effect modification [1, 2]. There are several methods to assess effect modification and the debate on which method is best is still ongoing [2–5]. In this article we focus on an invalid method to assess effect modification, which is often used in articles in health sciences journals [6], namely concluding that there is no effect modification if the confidence intervals of the subgroups are overlapping [7–9]. When assessing effect modification by looking at overlap of the 95% confidence intervals in subgroups, a type 1 error probability of 0.05 is often mistakenly assumed. In other words, if the confidence intervals are overlapping, the difference in effect estimates between the two subgroups is judged to be statistically insignificant. By using mathematical derivation, we calculated that the chance of finding non-overlapping 95% confidence intervals under the null hypothesis is 0.0056 if the variance of both effect estimates is equal and the effect estimates are independent (see Supplemental material for derivation of this probability). If the variance of the effect estimates is not equal, the chance of finding non-overlapping 95% confidence intervals can be calculated by taking into account ρ, i.e. the ratio between the standard deviations in the subgroups, σ2/σ1 (Supplementary material, formula (3)). Figure. 1 shows the relation between ρ and the type 1 error probability if the effect estimates are independent. If the effect estimates are not independent, the correlation coefficient between the effect estimates can also be accounted for (Supplementary material, formula (3)). Fig. 1 Relation between ρ, which is the ratio of σ2 and σ1, and the probability of non-overlapping confidence intervals under the null hypothesis (type 1 error) To arrive at a type 1 error probability of 0.05, 83.4% confidence intervals should be calculated around the effect estimates in subgroups if the variance is equal and the effect estimates are independent (see Supplementary material for derivation of this percentage). If the variance is not equal, ρ should be taken into account (Supplementary material, formula (11)). Figure. 2 shows the relation between ρ and the level of the confidence interval. If the effect estimates are not independent, the correlation coefficient should be taken into account (Supplementary material, formula (11)). Adapting the level of the confidence interval can be especially useful for graphical presentations, for example in meta-analyses [10]. However, it is necessary to explicitly and clearly state which percentage confidence interval is calculated and its meaning should be thoroughly explained to the reader. Many readers will still interpret this ‘new’ confidence interval as if it were a 95% confidence interval, because this percentage is so commonly used. To prevent such confusion, other methods to assess effect modification could be used, such as calculating a 95% confidence interval around the difference in effect estimates [8]. Fig. 2 Relation between ρ, which is the ratio of σ2 and σ1, and the percentage confidence intervals to be calculated to arrive at a type 1 error probability of 0.05 The assumption used in the formulas presented in the appendices is that the effect estimators in the subgroups are normally distributed. Assuming that epidemiologic effect measures, such as the odds ratio, risk ratio, hazard ratio and risk difference, follow a normal distribution, the methods presented can also be used for these epidemiologic measures. Note that the assumption for normality is generally unreasonable in small samples, but a satisfactory approximation in large samples.

Journal ArticleDOI
TL;DR: Strengths of associations and discrimination statistics suggested that WHR was the best predictor of cardiovascular events and mortality in patients with type-2 diabetes and BMI the worst.
Abstract: AIMS: The aim of this study was to compare the strength of associations and discrimination capability of body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) with cardiovascular disease risk in individuals with type-2 diabetes. METHODS AND RESULTS: Eleven thousand, one hundred and forty men and women were followed for a mean of 4.8 years. The Cox proportional hazard models were used to compute the hazard ratios and 95% confidence intervals (95% CI) for one standard deviation (SD) increase in baseline BMI (SD: 5 kg/m2), WC (SD: 13 cm) and WHR (SD: 0.08) with cardiovascular disease risk. After adjustment, hazard ratio (95% CI) for WC were 1.10 (1.03-1.18) for cardiovascular events, 1.13 (1.03-1.24) for coronary events, and 1.08 (0.98-1.19) for cardiovascular deaths. Estimates for WHR were 1.12 (1.05-1.19), 1.17 (1.08-1.28) and 1.19 (1.09-1.31). BMI was not related to any of these outcomes. Although the receiver operating characteristic curve could not differentiate between anthropometric variables (P values 0.24), the relative integrated discrimination improvement statistic showed an enhancement in the discrimination capabilities of models using WHR for cardiovascular outcomes, except for cerebrovascular events. CONCLUSION: Strengths of associations and discrimination statistics suggested that WHR was the best predictor of cardiovascular events and mortality in patients with type-2 diabetes and BMI the worst.

Journal ArticleDOI
TL;DR: Early VMS were not associated with increased CVD risk, and were associated with decreased risk of stroke, total CVD events, and all-cause mortality.
Abstract: Objective Emerging evidence suggests that women with menopausal vasomotor symptoms (VMS) have increased cardiovascular disease (CVD) risk as measured by surrogate markers. We investigated the relationships between VMS and clinical CVD events and all-cause mortality in the Women's Health Initiative Observational Study (WHI-OS).

Journal ArticleDOI
TL;DR: Among young adult patients with congenital heart disease, the use of six simple clinical parameters can accurately predict patients at relatively low or high risk of infective endocarditis.
Abstract: Aims The risk of infective endocarditis (IE) in adults with congenital heart disease is known to be increased, yet empirical risk estimates are lacking. We sought to predict the occurrence of IE in patients with congenital heart disease at the transition from childhood into adulthood. Methods and results We identified patients from the CONCOR national registry for adults with congenital heart disease. Potential predictors included patient characteristics, and complications and interventions in childhood. The outcome measure was the occurrence of IE up to the age of 40 and 60. A prediction model was derived using the Cox proportional hazards model and bootstrapping techniques. The model was transformed into a clinically applicable risk score. Of 10 210 patients, 233 (2.3%) developed adult-onset IE during 220 688 patient-years. Predictors of IE were gender, main congenital heart defect, multiple heart defects, and three types of complications in childhood. Up to the age of 40, patients with a low predicted risk (<3%) had an observed incidence of less than 1%; those with a high predicted risk (≥3%) had an observed incidence of 6%. The model also yielded accurate predictions up to the age of 60. Conclusion Among young adult patients with congenital heart disease, the use of six simple clinical parameters can accurately predict patients at relatively low or high risk of IE. After confirmation in other cohorts, application of the prediction model may lead to individually tailored medical surveillance and educational counselling, thus averting IE or enabling timely detection in adult patients with congenital heart disease.

Journal ArticleDOI
TL;DR: CIMT progression meets the criteria of a surrogate for cardiovascular disease endpoints and may be considered as a valid alternative for cardiovascular events as outcome.
Abstract: Background: Surrogate markers for cardiovascular disease might be of great value in observational research, clinical trials, and clinical practice. Carotid intima–media thickness (CIMT) is probably the most commonly used marker for atherosclerotic disease as an alternative for cardiovascular morbidity and mortality. A suitable marker for atherosclerosis, however, should meet several criteria before it can be validly used.Methods and results: We reviewed the literature following a set of criteria for a surrogate marker. These include a comparison with a ‘gold standard’; adequate reproducibility; cross-sectional relations with established risk factors and prevalent disease; relations with severity of atherosclerosis elsewhere in the arterial system; relations with the occurrence with future events; ability for a biomarker to change over time; ability to be affected by interventions over time; and relations between change over time in biomarker level and change in risk. A large number of studies from a varie...

Journal ArticleDOI
TL;DR: It is shown that serum protein profiles are already altered up to three years before breast cancer detection.
Abstract: Serum protein profiles have been investigated frequently to discover early biomarkers for breast cancer. So far, these studies used biological samples collected at or after diagnosis. This may limit these studies' value in the search for cancer biomarkers because of the often advanced tumor stage, and consequently risk of reverse causality. We present for the first time pre-diagnostic serum protein profiles in relation to breast cancer, using the Prospect-EPIC (European Prospective Investigation into Cancer and nutrition) cohort. In a nested case-control design we compared 68 women diagnosed with breast cancer within three years after enrollment, with 68 matched controls for differences in serum protein profiles. All samples were analyzed with SELDI-TOF MS (surface enhanced laser desorption/ionization time-of-flight mass spectrometry). In a subset of 20 case-control pairs, the serum proteome was identified and relatively quantified using isobaric Tags for Relative and Absolute Quantification (iTRAQ) and online two-dimensional nano-liquid chromatography coupled with tandem MS (2D-nanoLC-MS/MS). Two SELDI-TOF MS peaks with m/z 3323 and 8939, which probably represent doubly charged apolipoprotein C-I and C3a des-arginine anaphylatoxin (C3adesArg), were higher in pre-diagnostic breast cancer serum (p = 0.02 and p = 0.06, respectively). With 2D-nanoLC-MS/MS, afamin, apolipoprotein E and isoform 1 of inter-alpha trypsin inhibitor heavy chain H4 (ITIH4) were found to be higher in pre-diagnostic breast cancer (p < 0.05), while alpha-2-macroglobulin and ceruloplasmin were lower (p < 0.05). C3adesArg and ITIH4 have previously been related to the presence of symptomatic and/or mammographically detectable breast cancer. We show that serum protein profiles are already altered up to three years before breast cancer detection.

Journal ArticleDOI
TL;DR: Clinical data on the effects of inhaled long-acting beta-agonist use on the risk of mortality among patients with obstructive pulmonary disease was used to illustrate the impact of selection of confounding variables for adjustment based on baseline comparisons.
Abstract: In observational studies, selection of confounding variables for adjustment is often based on observed baseline incomparability. The aim of this study was to evaluate this selection strategy. We used clinical data on the effects of inhaled long-acting beta-agonist (LABA) use on the risk of mortality among patients with obstructive pulmonary disease to illustrate the impact of selection of confounding variables for adjustment based on baseline comparisons. Among 2,394 asthma and COPD patients included in the analyses, the LABA ever-users were considerably older than never-users, but cardiovascular co-morbidity was equally prevalent (19.9% vs. 19.9%). Adjustment for cardiovascular co-morbidity status did not affect the crude risk ratio (RR) for mortality: crude RR 1.19 (95% CI 0.93–1.51) versus RR 1.19 (95% CI 0.94–1.50) after adjustment for cardiovascular co-morbidity. However, after adjustment for age (RR 0.95, 95% CI 0.76–1.19), additional adjustment for cardiovascular co-morbidity status did affect the association between LABA use and mortality (RR 1.01, 95% CI 0.80–1.26). Confounding variables should not be discarded based on balanced distributions among exposure groups, because residual confounding due to the omission of confounding variables from the adjustment model can be relevant.

Journal ArticleDOI
15 Jun 2011-Heart
TL;DR: Using BNP alone with the currently recommended cut-off levels is not sufficient to make a reliable diagnosis of heart failure, but the ‘clinical plus BNP’ diagnostic model performed well in an independent cohort with comparable inclusion criteria.
Abstract: Background Diagnosing early stages of heart failure with mild symptoms is difficult. B-type natriuretic peptide (BNP) has promising biochemical test characteristics, but its diagnostic yield on top of readily available diagnostic knowledge has not been sufficiently quantified in early stages of heart failure. Objectives To quantify the added diagnostic value of BNP for the diagnosis of heart failure in a population relevant to GPs and validate the findings in an independent primary care patient population. Design Individual patient data meta-analysis followed by external validation. The additional diagnostic yield of BNP above standard clinical information was compared with ECG and chest x-ray results. Patients and methods Derivation was performed on two existing datasets from Hillingdon (n=127) and Rotterdam (n=149) while the UK Natriuretic Peptide Study (n=306) served as validation dataset. Included were patients with suspected heart failure referred to a rapid-access diagnostic outpatient clinic. Case definition was according to the ESC guideline. Logistic regression was used to assess discrimination (with the c-statistic) and calibration. Results Of the 276 patients in the derivation set, 30.8% had heart failure. The clinical model (encompassing age, gender, known coronary artery disease, diabetes, orthopnoea, elevated jugular venous pressure, crackles, pitting oedema and S3 gallop) had a c-statistic of 0.79. Adding, respectively, chest x-ray results, ECG results or BNP to the clinical model increased the c-statistic to 0.84, 0.85 and 0.92. Neither ECG nor chest x-ray added significantly to the ‘clinical plus BNP’ model. All models had adequate calibration. The ‘clinical plus BNP’ diagnostic model performed well in an independent cohort with comparable inclusion criteria (c-statistic=0.91 and adequate calibration). Using separate cut-off values for ‘ruling in’ (typically implying referral for echocardiography) and for ‘ruling out’ heart failure—creating a grey zone—resulted in insufficient proportions of patients with a correct diagnosis. Conclusion BNP has considerable diagnostic value in addition to signs and symptoms in patients suspected of heart failure in primary care. However, using BNP alone with the currently recommended cut-off levels is not sufficient to make a reliable diagnosis of heart failure.

Journal ArticleDOI
01 Apr 2011-Heart
TL;DR: Evidence from several Western countries suggests that among young adults (<55 years), CHD mortality rates are levelling out, and this is the first study to observe a subsequent increase in the pace of decline after a period of flattening.
Abstract: Background Coronary heart disease (CHD) mortality has steadily declined since the early 1970s in the Netherlands. However, in some Western countries the rate of decline in younger groups may be starting to plateau or even rise. Objective To examine trends in age-specific CHD mortality rates among Dutch adults from 1972 to 2007, with a particular focus on recent trends for the younger age groups Methods Data for all CHD deaths (1972e2007) in the Netherlands were grouped by year, sex, age. A joinpoint regression was fitted to each age-sex-group to detect points in time at which significant changes in the trends occur. For every time period, the linear slope of the trend, p value, observed number of deaths, CHD mortality rates and change in the CHD mortality rate were calculated. Results Between 1972 and 2007, the age-adjusted CHD mortality rates decreased overall by 76% in both men and women. In men (35e54 years), the change in CHD mortality rate in the period 1980e1993 was 0.53 but attenuated in period 1993e1999: 0.16. In women (35e54 years) the decline likewise attenuated to 0.44 in period 1979e1989: and 0.05 in period 1989e2000. After 1999e2000, CHD mortality rate further declined in both men (period 1999e2007: 0.46) and women (period 2000e2007: 0.38). Conclusions Evidence from several Western countries suggests that among young adults (<55 years), CHD mortality rates are levelling out. In this study, similar attenuation of the decline in CHD mortality among young adults in the Netherlands has been observed. Furthermore, this is the first study to observe a subsequent increase in the pace of decline after a period of flattening. In order to better explain these encouraging changes in CHD mortality rates, a detailed analysis of recent changes in cardiovascular risk factors and treatments is now urgently required.

Journal ArticleDOI
TL;DR: In this paper, the performance of automated B-type natriuretic peptide (BNP) assays is evaluated in patients suspected of new slow-onset heart failure.

01 Jan 2011
TL;DR: A new meta-analysis of GWAS data that includes staged follow-up genotyping to identify additional BP loci is reported, providing new insights into the genetics and biology of BP, and suggest novel potential therapeutic pathways for cardiovascular disease prevention.
Abstract: Blood pressure (BP) is a heritable trait1 influenced by multiple biological pathways and is responsive to environmental stimuli. Over one billion people worldwide have hypertension (BP ≥140 mm Hg systolic [SBP] or ≥90 mm Hg diastolic [DBP])2. Even small increments in BP are associated with increased risk of cardiovascular events3. This genome-wide association study of SBP and DBP, which used a multi-stage design in 200,000 individuals of European descent, identified 16 novel loci: six of these loci contain genes previously known or suspected to regulate BP (GUCY1A3-GUCY1B3; NPR3-C5orf23; ADM; FURIN-FES; GOSR2; GNAS-EDN3); the other 10 provide new clues to BP physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke, and coronary artery disease, but not kidney disease or kidney function. We also observed associations with BP in East Asian, South Asian, and African ancestry individuals. Our findings provide new insights into the genetics and biology of BP, and suggest novel potential therapeutic pathways for cardiovascular disease prevention. Genetic approaches have advanced the understanding of biological pathways underlying inter-individual variation in BP. For example, studies of rare Mendelian BP disorders have identified multiple defects in renal sodium handling pathways4. More recently two genomewide association studies (GWAS), each of >25,000 individuals of European-ancestry, identified 13 loci associated with SBP, DBP, and hypertension5,6. We now report results of a new meta-analysis of GWAS data that includes staged follow-up genotyping to identify additional BP loci. Primary analyses evaluated associations between 2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and SBP and DBP in 69,395 individuals of European ancestry from 29 studies (Supplementary Materials Sections 1–3, Supplementary Tables 1– 2). Following GWAS meta-analysis, we conducted a three-stage validation experiment that made efficient use of available genotyping resources, to follow up top signals in up to 133,661 additional individuals of European descent (Supplementary Fig. 1 and Supplementary Materials Section 4). Twenty-nine independent SNPs at 28 loci were significantly associated with SBP, DBP, or both in the meta-analysis combining discovery and follow up data (Fig. 1, Table 1, Supplementary Figs 2–3, Supplementary Tables 3–5). All 29 SNPs attained association P <5×10−9, an order of magnitude beyond the standard genome-wide significance level for a single stage experiment (Table 1). Sixteen of these 29 associations were novel (Table 1). Two associations were near the FURIN and GOSR2 genes; prior targeted analyses of variants in these genes suggested they Note added in proof: Since this manuscript was submitted, Kato et al published a BP GWAS in East Asians that identified a SNP highly correlated to the SNP we report at the NPR3-c5orf23 locus28. Author contributions Full author contributions and roles are listed in the Supplementary Materials Section 19. NIH Public Access Author Manuscript Nature. Author manuscript; available in PMC 2012 May 01. Published in final edited form as: Nature. ; 478(7367): 103–109. doi:10.1038/nature10405. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript may be BP loci7,8. At the CACNB2 locus we validated association for a previously reported6 SNP rs4373814 and detected a novel independent association for rs1813353 (pairwise r2 =0.015 in HapMap CEU). Of our 13 previously reported associations5,6, only the association at PLCD3 was not supported by the current results (Supplementary Table 4). Some of the associations are in or near genes involved in pathways known to influence BP (NPR3, GUCY1A3-GUCY1B3, ADM, GNAS-EDN3, NPPA-NPPB, and CYP17A1; Supplementary Fig. 4). Twenty-two of the 28 loci did not contain genes that were a priori strong biological candidates. As expected from prior BP GWAS results, the effects of the novel variants on SBP and DBP were small (Fig. 1 and Table 1). For all variants, the observed directions of effects were concordant for SBP, DBP, and hypertension (Fig. 1, Table 1, Supplementary Fig. 3). Among the genes at the genome-wide significant loci, only CYP17A1, previously implicated in Mendelian congenital adrenal hyperplasia and hypertension, is known to harbour rare variants that have large effects on BP9. We performed several analyses to identify potential causal alleles and mechanisms. First, we looked up the 29 genome-wide significant index SNPs and their close proxies (r2>0.8) among cis-acting expression SNP (eSNP) results from multiple tissues (Supplementary Materials Section 5). For 13/29 index SNPs, we found association between nearby eSNP variants and expression level of at least one gene transcript (10−4 > p > 10−51, Supplementary Table 6). In 5 cases, the index BP SNP and the best eSNP from a genomewide survey were identical, highlighting potential mediators of the SNP-BP associations. Second, because changes in protein sequence are strong a priori candidates to be functional, we sought non-synonymous coding SNPs that were in high LD (r2 >0.8) with the 29 index SNPs. We identified such SNPsat 8 loci (Table 1, Supplementary Materials Section 6, Supplementary Table 7). In addition we performed analyses testing for differences in genetic effect according to body mass index (BMI) or sex, and analyses of copy number variants, pathway enrichment, and metabolomic data, but we did not find any statistically significant results (Supplementary Materials Sections 7–9, Supplementary Tables 8–10). We evaluated whether the BP variants we identified in Europeans were associated with BP in individuals of East Asian (N=29,719), South Asian (N=23,977), and African (N=19,775) ancestries (Table 1, Supplementary Tables 11–13). We found significant associations in individuals of East Asian ancestry for SNPs at 9 loci and in individuals of South Asian ancestry for SNPs at 6 loci; some have been reported previously (Supplementary Tables 12 and 15). The lack of significant association for individual SNPs may reflect small sample sizes, differences in allele frequencies or LD patterns, imprecise imputation for some ancestries using existing reference samples, or a genuinely different underlying genetic architecture. Because of limited power to detect effects of individual variants in the smaller non-European samples, we created genetic risk scores for SBP and DBP incorporating all 29 BP variants weighted according to effect sizes observed in the European samples. In each non-European ancestry group, risk scores were strongly associated with SBP (P=1.1×10−40 in East Asian, P=2.9×10−13 in South Asian, P=9.8×10−4 in African ancestry individuals) and DBP (P=2.9×10−48, P=9.5×10−15, and P=5.3×10−5, respectively; Supplementary Table 13). We also created a genetic risk score to assess association of the variants in aggregate with hypertension and with clinical measures of hypertensive complications including left ventricular mass, left ventricular wall thickness, incident heart failure, incident and prevalent stroke, prevalent coronary artery disease (CAD), kidney disease, and measures of kidney function, using results from other GWAS consortia (Table 2, Supplementary Materials Sections 10–11, Supplementary Table 14). The risk score was weighted using the average of Page 2 Nature. Author manuscript; available in PMC 2012 May 01. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript SBP and DBP effects for the 29 SNPs. In an independent sample of 23,294 women10, an increase of 1 standard deviation in the genetic risk score was associated with a 21% increase in the odds of hypertension (95% CI 19%–28%; Table 2, Supplementary Table 14). Among individuals in the top decile of the risk score, the prevalence of hypertension was 29% compared with 16% in the bottom decile (odds ratio 2.09, 95% CI 1.86–2.36). Similar results were observed in an independent hypertension case-control sample (Table 2). In our study, individuals in the top compared to bottom quintiles of genetic risk score differed by 4.6 mm Hg SBP and 3.0 mm Hg DBP, differences that approach population-averaged BP treatment effects for a single antihypertensive agent11. Epidemiologic data have shown that differences in SBP and DBP of this magnitude, across the population range of BP, are associated with an increase in cardiovascular disease risk3. Consistent with this and in line with findings from randomized trials of BP-lowering medication in hypertensive patients12,13, the genetic risk score was positively associated with left ventricular wall thickness (P=6.0×10−6), occurrence of stroke (P=3.3×10−5) and CAD (P=8.1×10−29). The same genetic risk score was not, however, significantly associated with chronic kidney disease or measures of kidney function, even though these renal outcomes were available in a similar sample size as for the other outcomes (Table 2). The absence of association with kidney phenotypes could be explained by a weaker causal relation of BP with kidney phenotypes than with CAD and stroke. This finding is consistent with the mismatch between observational data that show a positive association of BP with kidney disease, and clinical trial data that show inconsistent evidence of benefit of BP lowering on kidney disease prevention in patients with hypertension14. Thus, several lines of evidence converge to suggest that BP elevation may in part be a consequence rather than a cause of sub-clinical kidney disease. Our discovery meta-analysis (Supplementary Fig. 2) suggests an excess of modestly significant (10−5


Journal ArticleDOI
TL;DR: Evidence is found suggestive of decreasing volumes of the putamen and nucleus accumbens over time after discontinuation of medication, which might suggest that discontinuation reverses effects of atypical medication.
Abstract: The influence of antipsychotic medication on brain morphology in schizophrenia may confound interpretation of brain changes over time. We aimed to assess the effect of discontinuation of atypical antipsychotic medication on change in brain volume in patients. Sixteen remitted, stable patients with first-episode schizophrenia, schizoaffective or schizophreniform disorder and 20 healthy controls were included. Two magnetic resonance imaging brain scans were obtained from all subjects with a 1-year interval. The patients either discontinued (n = 8) their atypical antipsychotic medication (olanzapine, risperidone, or quetiapine) or did not (n = 8) discontinue during the follow-up period. Intracranial volume and volumes of total brain, cerebral gray and white matter, cerebellum, third and lateral ventricle, nucleus caudatus, nucleus accumbens, and putamen were obtained. Multiple linear regression analyses were used to assess main effects for group (patient-control) and discontinuation (yes-no) for brain volume (change) while correcting for age, sex, and intracranial volume. Decrease in cerebral gray matter and caudate nucleus volume over time was significantly more pronounced in patients relative to controls. Our data suggest decreases in the nucleus accumbens and putamen volumes during the interval in patients who discontinued antipsychotic medication, whereas increases were found in patients who continued their antipsychotics. We confirmed earlier findings of excessive gray matter volume decrements in patients with schizophrenia compared with normal controls. We found evidence suggestive of decreasing volumes of the putamen and nucleus accumbens over time after discontinuation of medication. This might suggest that discontinuation reverses effects of atypical medication.

Journal ArticleDOI
16 Jun 2011-PLOS ONE
TL;DR: In this paper, the authors determined the frequency of use of ORs and the percentage of overestimation of the OR as compared with its accompanying RR in published RCTs, and assessed how often regression models that calculate RRs were used.
Abstract: Background In randomized controlled trials (RCTs), the odds ratio (OR) can substantially overestimate the risk ratio (RR) if the incidence of the outcome is over 10%. This study determined the frequency of use of ORs, the frequency of overestimation of the OR as compared with its accompanying RR in published RCTs, and we assessed how often regression models that calculate RRs were used. Methods We included 288 RCTs published in 2008 in five major general medical journals (Annals of Internal Medicine, British Medical Journal, Journal of the American Medical Association, Lancet, New England Journal of Medicine). If an OR was reported, we calculated the corresponding RR, and we calculated the percentage of overestimation by using the formula . Results Of 193 RCTs with a dichotomous primary outcome, 24 (12.4%) presented a crude and/or adjusted OR for the primary outcome. In five RCTs (2.6%), the OR differed more than 100% from its accompanying RR on the log scale. Forty-one of all included RCTs (n = 288; 14.2%) presented ORs for other outcomes, or for subgroup analyses. Nineteen of these RCTs (6.6%) had at least one OR that deviated more than 100% from its accompanying RR on the log scale. Of 53 RCTs that adjusted for baseline variables, 15 used logistic regression. Alternative methods to estimate RRs were only used in four RCTs. Conclusion ORs and logistic regression are often used in RCTs and in many articles the OR did not approximate the RR. Although the authors did not explicitly misinterpret these ORs as RRs, misinterpretation by readers can seriously affect treatment decisions and policy making.

Journal ArticleDOI
TL;DR: WHO guidelines based national mortality registries lack the specificity and completeness needed for accurate research on causes of death in adult patients with congenital heart disease (CHD).

Journal ArticleDOI
TL;DR: Subclinical vascular calcification on CT is a strong predictor of incident CVD events in a routine clinical care population and should be included in routine diagnostic chest CT investigations.
Abstract: An increase in the number of CT investigations will likely result in a an increase in unrequested information. Clinical relevance of these findings is unknown. This is the first follow-up study to investigate the prognostic relevance of subclinical coronary (CAC) and aortic calcification (TAC) as contained in routine diagnostic chest CT in a clinical care population. The follow-up of 10,410 subjects (>40 years) from a multicentre, clinical care-based cohort of patients included 240 fatal to 275 non-fatal cardiovascular disease (CVD) events (mean follow-up 17.8 months). Patients with a history of CVD were excluded. Coronary (0–12) and aortic calcification (0–8) were semi-quantitatively scored. We used Cox proportional-hazard models to compute hazard ratios to predict CVD events. CAC and TAC were significantly and independently predictive of CVD events. Compared with subjects with no calcium, the adjusted risk of a CVD event was 3.7 times higher (95% CI, 2.7–5.2) among patients with severe coronary calcification (CAC score ≥6) and 2.7 times higher (95% CI, 2.0–3.7) among patients with severe aortic calcification (TAC score ≥5). Subclinical vascular calcification on CT is a strong predictor of incident CVD events in a routine clinical care population.

Journal ArticleDOI
TL;DR: Haemosiderin seemed associated with the time between assessment and last bleed; joints that had suffered a bleed long before MRI had hardly haemOSiderin, while those with a recent bleed showed haemosIDERin, suggesting joint damage may be reversible.
Abstract: The clinical relevance of subtle changes on magnetic resonance imaging (MRI) for evaluating haemophilia treatment is unknown. To determine the relationship of findings on MRI with joint function and bleeding in joints with apparently very mild arthropathy, a prospective study was performed. Knees and ankles of 26 patients, 13-26 years, were scanned. Two blinded radiologists scored the MRI (IPSG consensus score) and the radiography [Pettersson score (PS)]. Clinical function (HJHS) was scored by one physiotherapist. Life-time number of bleeds was collected from patient files. Of 104 joints scanned, three were excluded because of previous arthrodesis or trauma. Remaining 101 MRI scores correlated weakly with clinical function (r = 0.27, P = 0.01) and less with lifetime number of bleeds (r = 0.16, P = 0.14). MRI scores were 0 in 58 joints, including 27 with major bleeds. In three joints of patients playing intensive sports MRI showed minor changes (MRI score = 1) in the absence of bleeds. Agreement was reasonable between PS and MRI score (r = 0.41, P < 0.01). In 30% of joints, MRI detected abnormalities in soft-tissue and cartilage, while PS was 0 points. No evidence of occult haemorrhages was found. Instead, we found no abnormalities on MRI in 43 joints with a history of repeated joint bleeding. Haemosiderin seemed associated with the time between assessment and last bleed; joints that had suffered a bleed long before MRI had hardly haemosiderin, while those with a recent bleed showed haemosiderin, suggesting joint damage may be reversible. Abnormalities detected by MRI, but not by PS were minor and their clinical implications are not yet clear.

Journal ArticleDOI
TL;DR: Discontinuation of antipsychotic medication markedly increases the risk of relapse in stable remitted first-episode schizophrenia patients.
Abstract: Objective. To assess the effect of withdrawal of antipsychotic treatment on relapse risk in remitted fi rst-episode schizophrenia patients. Methods. First-episode 1-year stable and remitted outpatients with a schizophrenic disorder were randomly allocated to continuation of their antipsychotic regimen for at least 6 months ( N � 9), or gradual withdrawal ( N � 11). Primary outcome was the difference in cumulative relapse-free survival at 9 months. Results. Recruitment was terminated prematurely on 26 October 2005. The cumulative relapse-free survival was 88% (SE � 0.12) in the continuation and 18% (SE � 0.12) in the discontinuation group ( P � 0.001) at 9 months follow-up. Conclusions . Discontinuation of antipsychotic medication markedly increases the risk of relapse in stable remitted fi rst-episode schizophrenia patients. In future studies the topics of safety monitoring and sampling of patients should receive extra attention.