Publications by authors named "Saskia le Cessie"

252 Publications

Evaluation of the Value of Waist Circumference and Metabolomics in the Estimation of Visceral Adipose Tissue.

Am J Epidemiol 2022 Jan 6. Epub 2022 Jan 6.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

Visceral adipose tissue (VAT) is a strong prognostic factor for cardiovascular disease and a potential target for cardiovascular risk stratification. Because VAT is difficult to measure in clinical practice, we estimated prediction models with predictors routinely measured in general practice and VAT as outcome using ridge regression in 2,501 middle-aged participants from the Netherlands Epidemiology of Obesity study, 2008-2012. Adding waist circumference and other anthropometric measurements on top of the routinely measured variables improved the optimism-adjusted R2 from 0.50 to 0.58 with a decrease in the root-mean-square error (RMSE) from 45.6 to 41.5 cm2 and with overall good calibration. Further addition of predominantly lipoprotein-related metabolites from the Nightingale platform did not improve the optimism-corrected R2 and RMSE. The models were externally validated in 370 participants from the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS, 2006-2009) and 1,901 participants from the Multi-Ethnic Study of Atherosclerosis (MESA, 2000-2007). Performance was comparable to the development setting in PIVUS (R2: 0.63, RMSE: 42.4 cm2, calibration slope: 0.94) but lower in MESA (R2: 0.44, RMSE: 60.7 cm2, calibration slope: 0.75). Our findings indicate that the estimation of VAT with routine clinical measurements can be substantially improved by incorporating waist circumference but not by metabolite measurements.
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http://dx.doi.org/10.1093/aje/kwab298DOI Listing
January 2022

Association of cognitive function with increased risk of cancer death and all-cause mortality: Longitudinal analysis, systematic review, and meta-analysis of prospective observational studies.

PLoS One 2022 7;17(1):e0261826. Epub 2022 Jan 7.

Department of Gerontology and Geriatrics, Leiden University Medical Centre, Leiden, The Netherlands.

Background: Disturbed cognitive function is associated with several causes of mortality; however, the association between cognitive function and the risk of cancer death has not been extensively investigated yet. We aimed to evaluate the association of cognitive function with the risk of cancer death and all-cause mortality in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) and Leiden 85-plus Study. Additionally, a systematic review and meta-analysis of longitudinal studies were conducted to evaluate the association of cognitive function and risk of cancer death.

Methods: Risk of cancer death and all-cause mortality were reported using hazard ratios (HRs) with 95% confidence interval (CI) in tertiles of cognitive function of PROSPER and Leiden85-Plus Study. Additionally, PubMed, Embase, Web of Science, Cochrane, PsycINFO, Academic Search Premier, CINHAL, and Emcare were searched up to November 1st, 2020 to perform a systematic review and meta-analysis. The relative risks (RRs) with 95%CI of cancer death per each standard deviation lower performance in cognitive measurements were calculated.

Results: Participants of PROSPER had 1.65-fold (95%CI 1.11-2.47) greater risk of cancer death (P for trend = 0.016) and 1.85-fold (95%CI 1.46-2.34) higher risk of all-cause mortality (P for trend<0.001), in multivariable models. Results of the Leiden-85 Plus Study showed that subjects with MMSE score below 24 had a lower chance of cancer death (HR 0.79, 95%CI 0.36-1.70, P for trend = 0.820) but had 2.18-fold (95%CI 1.57-3.02) higher risk of all-cause mortality compared to the reference group (P for trend<0.001). Besides, the results of systematic review and meta-analysis showed that per each standard deviation lower performance in cognitive function, individuals were at a 10% higher chance of cancer death (RR 1.10, 95%CI 1.00-1.20, P-value = 0.044).

Conclusions: Lower cognitive function performance is associated with a marginally increased risk of cancer death, in line with a significantly greater risk of all-cause mortality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0261826PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8741047PMC
January 2022

Toward more accurate prediction of future pregnancy outcome in couples with unexplained recurrent pregnancy loss: taking both partners into account.

Fertil Steril 2022 Jan 1;117(1):144-152. Epub 2021 Dec 1.

Department of Gynaecology and Obstetrics, Leiden University Medical Center, Leiden, the Netherlands.

Objective: To identify, besides maternal age and the number of previous pregnancy losses, additional characteristics of couples with unexplained recurrent pregnancy loss (RPL) that improve the prediction of an ongoing pregnancy.

Design: Hospital-based cohort study in couples who visited specialized RPL units of two academic centers between 2012 and 2020.

Setting: Two academic centers in the Netherlands.

Patients: Clinical data from 526 couples with unexplained RPL were used in this study.

Intervention(s): None.

Main Outcome Measures: The final model to estimate the chance of a subsequent ongoing pregnancy was determined using a backward selection process and internally validated using bootstrapping. Model performance was assessed in terms of calibration and discrimination (area under the receiver operating characteristic curve).

Results: Subsequent ongoing pregnancy was achieved in 345 of 526 couples (66%). The number of previous pregnancy losses, maternal age, paternal age, maternal body mass index, paternal body mass index, maternal smoking status, and previous in vitro fertilization/intracytoplasmic sperm injection treatment were predictive of the outcome. The optimism-corrected area under the receiver operating characteristic curve was 0.63 compared with 0.57 when using only the number of previous pregnancy losses and maternal age.

Conclusions: The identification of additional predictors of a subsequent ongoing pregnancy after RPL, including male characteristics, is significant for both clinicians and couples with RPL. At the same time, we showed that the predictive ability of the current model is still limited and more research is warranted to develop a model that can be used in clinical practice.
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http://dx.doi.org/10.1016/j.fertnstert.2021.08.037DOI Listing
January 2022

Coronavirus disease 2019 and peripheral blood eosinophil counts: a retrospective study.

Infection 2021 Dec 8;49(6):1325-1329. Epub 2021 Oct 8.

Department of Internal Medicine, Groene Hart Ziekenhuis, Bleulandweg 10, 2803 HH, Gouda, The Netherlands.

Purpose: Eosinopenia has been described in COVID-19. With this study, we aim to study the peripheral blood eosinophil counts in COVID-19 patients and to investigate whether there is an association between the peripheral blood eosinophil counts and disease severity of COVID-19.

Methods: We revised the electronical medical records of confirmed COVID-19 patients with polymerase chain reaction (PCR) assays in the Groene Hart Ziekenhuis, Gouda, The Netherlands. We divided patients in mild, moderate and severe groups based on clinical severity of COVID-19. Clinical severity was based on the therapy needed and the outcome of patients. We compared clinical characteristics, laboratory results and outcome between the three groups.

Results: Of the 230 patients included in this study, the mild, moderate and severe groups consisted of 16.5%, 45.7% and 37.8% of the included patients, respectively. The mean age was 68 years (IQR 57-78). 63% of patients were male. A significant decrease in the peripheral eosinophil counts was found corresponding to the increase of COVID-19 severity. In the mild, moderate and severe groups, the percentage of patients with eosinopenia was 73.7%, 86.7% and 94.3%, respectively (p value 0.002).

Conclusion: Eosinopenia is significantly more frequent present in patients with a severe COVID-19.
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http://dx.doi.org/10.1007/s15010-021-01710-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500265PMC
December 2021

Mendelian randomization study of the relation between adiponectin and heart function, unravelling the paradox.

Peptides 2021 12 28;146:170664. Epub 2021 Sep 28.

Department of Cardiology, Department of Gerontology and Geriatrics, Leiden University Medical Center, Netherlands. Electronic address:

High adiponectin concentrations are generally regarded as beneficial with regard to cardiometabolic health, but have been paradoxically associated with increased cardiovascular disease risk, specifically heart failure, in individuals at high cardiovascular risk. We aimed to investigate the association between adiponectin and heart function parameters, and inversely, we estimated the effect of genetically-determined heart function and NT-proBNP as the main marker of heart failure on adiponectin using Mendelian randomisation. Observational analyses between adiponectin and measures of heart function, i.e. E/A ratio, left, and right ventricular ejection fraction, were performed in participants of the Netherlands Epidemiology of Obesity (NEO) study, assessed by MRI of the heart (n = 1,138). Two-sample Mendelian randomisation analyses were conducted to estimate the effect of NT-proBNP and heart function on adiponectin concentrations using publicly-available summary statistics (ADIPOGen; the PLATO trial). The mean (standard deviation) age was 56 (6) years and mean body mass index was 26 (4) kg/m. Per five μg/mL higher adiponectin, the E/A ratio was -0.05 (95 % CI: -0.10, -0.01) lower, left ventricle ejection fraction was -0.5 % (95 % CI: -1.1, 0.1) lower, and right ventricle ejection fraction was 0.5 % (95 % CI: -0.1, 1.2) higher. Genetically-determined NT-proBNP was causally related to adiponectin concentrations in ADIPOGen: per doubling of genetically-determined NT-proBNP, adiponectin concentrations were 11.4 % (95 % CI: 1.7, 21.6) higher. With causal MR methods we showed that NT-proBNP affects adiponectin concentrations, while adiponectin is not associated with heart function parameters. Therefore, reverse causation may explain the adiponectin paradox observed in previous studies.
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http://dx.doi.org/10.1016/j.peptides.2021.170664DOI Listing
December 2021

The PRolaCT studies - a study protocol for a combined randomised clinical trial and observational cohort study design in prolactinoma.

Trials 2021 Sep 25;22(1):653. Epub 2021 Sep 25.

Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Albinusdreef 2, 2333ZA, Leiden, The Netherlands.

Background: First-line treatment for prolactinomas is a medical treatment with dopamine agonists (DAs), which effectively control hyperprolactinaemia in most patients, although post-withdrawal remission rates are approximately 34%. Therefore, many patients require prolonged DA treatment, while side effects negatively impact health-related quality of life (HRQoL). Endoscopic transsphenoidal resection is reserved for patients with severe side effects, or with DA-resistant prolactinoma. Surgery has a good safety profile and high probability of remission and may thus deserve a more prominent place in prolactinoma treatment. The hypothesis for this study is that early or upfront surgical resection is superior to DA treatment both in terms of HRQoL and remission rate in patients with a non-invasive prolactinoma of limited size.

Methods: We present a combined randomised clinical trial and observational cohort study design, which comprises three unblinded randomised controlled trials (RCTs; PRolaCT-1, PRolaCT-2, PRolaCT-3), and an observational study arm (PRolaCT-O) that compare neurosurgical counselling, and potential subsequent endoscopic transsphenoidal adenoma resection, with current standard care. Patients with a non-invasive prolactinoma (< 25 mm) will be eligible for one of three RCTs based on the duration of pre-treatment with DAs: PRolaCT-1: newly diagnosed, treatment-naïve patients; PRolaCT-2: patients with limited duration of DA treatment (4-6 months); and PRolaCT-3: patients with persisting prolactinoma after DA treatment for > 2 years. PRolaCT-O will include patients who decline randomisation, due to e.g. a clear treatment preference. Primary outcomes are disease remission after 36 months and HRQoL after 12 months.

Discussion: Early or upfront surgical resection for patients with a limited-sized prolactinoma may be a reasonable alternative to the current standard practice of DA treatment, which we will investigate in three RCTs and an observational cohort study. Within the three RCTs, patients will be randomised between neurosurgical counselling and standard care. The observational study arm will recruit patients who refuse randomisation and have a pronounced treatment preference. PRolaCT will collect randomised and observational data, which may facilitate a more individually tailored practice of evidence-based medicine.

Trial Registration: US National Library of Medicine registry (ClinicalTrials.gov) NCT04107480 . Registered on 27 September 2019, registered retrospectively (by 2 months).
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http://dx.doi.org/10.1186/s13063-021-05604-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465768PMC
September 2021

Associations of metabolomic profiles with circulating vitamin E and urinary vitamin E metabolites in middle-aged individuals.

Nutrition 2022 Jan 29;93:111440. Epub 2021 Jul 29.

Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.

Vitamin E (α-tocopherol [α-TOH]) is transported in lipoprotein particles in blood, but little is known about the transportation of its oxidized metabolites. In the Netherlands Epidemiology of Obesity Study, we aimed to investigate the associations of 147 circulating metabolomic measures obtained through targeted nuclear magnetic resonance with serum α-TOH and its urinary enzymatic (α-CEHC) and oxidized (α-TLHQ) metabolites from 24-h urine quantified by liquid chromatography with tandem mass spectrometry. Multivariable linear regression analyses, in which multiple testing was taken into account, were performed to assess associations between metabolomic measures (determinants; standardized to mean = 0, SD = 1) and vitamin E metabolites (outcomes), adjusted for demographic factors. We analyzed 474 individuals (55% women, 45% men) with a mean (SD) age of 55.7 (6.0) y. Out of 147 metabolomic measures, 106 were associated (P < 1.34 × 10) with serum α-TOH (median β [interquartile range] = 0.416 [0.383-0.466]), predominantly lipoproteins associated with higher α-TOH. The associations of metabolomic measures with urinary α-CEHC have directions similar to those with α-TOH, but effect sizes were smaller and non-significant (median β [interquartile range] = 0.065 [0.047-0.084]). However, associations of metabolomic measures with urinary α-TLHQ were markedly different from those with both serum α-TOH and urinary α-CEHC, with negative and small-to-null relations to most very-low-density lipoproteins and amino acids. Therefore, our results highlight the differences in the lipoproteins involved in the transportation of circulating α-TOH and oxidized vitamin E metabolites. This indicates that circulating α-TOH may be representative of the enzymatic but not the antioxidative function of vitamin E.
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http://dx.doi.org/10.1016/j.nut.2021.111440DOI Listing
January 2022

Factors associated with physical activity among COPD patients with mild or moderate airflow obstruction.

Monaldi Arch Chest Dis 2021 Sep 14. Epub 2021 Sep 14.

Department of Pulmonary Medicine, University Hospital Essen, Ruhrlandklinik, University Duisburg-Essen, Essen.

Physical inactivity is already present among patients with chronic obstructive pulmonary disease (COPD) of mild or moderate airflow obstruction. Most previous studies that reported on determinants of physical activity in COPD included patients with severe COPD. Therefore, the aim of this study was to explore which patient characteristics were related with physical activity in COPD patients with mild or moderate airflow obstruction. Cross-sectional analyses were performed on patients selected from the population-based Netherlands Epidemiology of Obesity study. Patients were included if they had a physician-diagnosed COPD GOLD 0-2 or had newly diagnosed COPD GOLD 1-2. Physical activity was evaluated using the Short Questionnaire to Assess Health-Enhancing Physical Activity (SQUASH) questionnaire and reported in hours per week of metabolic equivalents (MET-h/week). Associations between sociodemographic, lifestyle, clinical and functional characteristics were examined using regression analysis. 323 patients were included in research (77 with physician-diagnosed and 246 with newly diagnosed COPD). We found that physical activity was positively associated with pulmonary function: FEV1 (regression coefficient 0.40 (95% CI 0.09,0.71)) and FVC (regression coefficient 0.34 (95% CI 0.06,0.61)). Physical activity was associated with anxiety (regression coefficient =0.9 (95% CI 0.3,1.6)) only for physician-diagnosed patients. Lung function and anxiety level determine level of physical activity among COPD patients with mild or moderate airflow obstruction. Thus, integrating it into the physical activity plans could help to increase physical activity level of the patients.
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http://dx.doi.org/10.4081/monaldi.2021.1891DOI Listing
September 2021

COVID RADAR app: Description and validation of population surveillance of symptoms and behavior in relation to COVID-19.

PLoS One 2021 30;16(6):e0253566. Epub 2021 Jun 30.

Department of Public Health & Primary Care/LUMC Campus, The Hague Leiden University Medical Center, The Hague, Netherlands.

Background: Monitoring of symptoms and behavior may enable prediction of emerging COVID-19 hotspots. The COVID Radar smartphone app, active in the Netherlands, allows users to self-report symptoms, social distancing behaviors, and COVID-19 status daily. The objective of this study is to describe the validation of the COVID Radar.

Methods: COVID Radar users are asked to complete a daily questionnaire consisting of 20 questions assessing their symptoms, social distancing behavior, and COVID-19 status. We describe the internal and external validation of symptoms, behavior, and both user-reported COVID-19 status and state-reported COVID-19 case numbers.

Results: Since April 2nd, 2020, over 6 million observations from over 250,000 users have been collected using the COVID Radar app. Almost 2,000 users reported having tested positive for SARS-CoV-2. Amongst users testing positive for SARS-CoV-2, the proportion of observations reporting symptoms was higher than that of the cohort as a whole in the week prior to a positive SARS-CoV-2 test. Likewise, users who tested positive for SARS-CoV-2 showed above average risk social-distancing behavior. Per-capita user-reported SARS-CoV-2 positive tests closely matched government-reported per-capita case counts in provinces with high user engagement.

Discussion: The COVID Radar app allows voluntarily self-reporting of COVID-19 related symptoms and social distancing behaviors. Symptoms and risk behavior increase prior to a positive SARS-CoV-2 test, and user-reported case counts match closely with nationally-reported case counts in regions with high user engagement. These results suggest the COVID Radar may be a valid instrument for future surveillance and potential predictive analytics to identify emerging hotspots.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253566PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244909PMC
July 2021

The Relation Between Adult Weight Gain, Adipocyte Volume, and the Metabolic Profile at Middle Age.

J Clin Endocrinol Metab 2021 10;106(11):e4438-e4447

Department of Clinical Epidemiology, Leiden University Medical Center, 2300RC Leiden, the Netherlands.

Context: Weight gain during adulthood increases cardiometabolic disease risk, possibly through adipocyte hypertrophy.

Objective: We aimed to study the specific metabolomic profile of adult weight gain, and to examine its association with adipocyte volume.

Methods: Nuclear magnetic resonance-based metabolomics were measured in the Netherlands Epidemiology of Obesity (NEO) study (n = 6347, discovery) and Oxford Biobank (n = 6317, replication). Adult weight gain was calculated as the absolute difference between body mass index (BMI) at middle age and recalled BMI at age 20 years. We performed linear regression analyses with both exposures BMI at age 20 years and weight gain, and separately with BMI at middle age in relation to 149 serum metabolomic measures, adjusted for age, sex, and multiple testing. Additionally, subcutaneous abdominal adipocyte biopsies were collected in a subset of the Oxford Biobank (n = 114) to estimate adipocyte volume.

Results: Mean (SD) weight gain was 4.5 (3.7) kg/m2 in the NEO study and 3.6 (3.7) kg/m2 in the Oxford Biobank. Weight gain, and not BMI at age 20 nor middle age, was associated with concentrations of 7 metabolomic measures after successful replication, which included polyunsaturated fatty acids, small to medium low-density lipoproteins, and total intermediate-density lipoprotein. One SD weight gain was associated with 386 μm3 (95% CI, 143-629) higher median adipocyte volume. Adipocyte volume was associated with lipoprotein particles specific for adult weight gain.

Conclusion: Adult weight gain is associated with specific metabolomic alterations of which the higher lipoprotein concentrations were likely contributed by larger adipocyte volumes, presumably linking weight gain to cardiometabolic disease.
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http://dx.doi.org/10.1210/clinem/dgab477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530710PMC
October 2021

Developing an algorithm for the diagnosis of abnormal vaginal discharge in a dutch clinical setting: a pilot study.

Diagn Microbiol Infect Dis 2021 Sep 17;101(1):115431. Epub 2021 May 17.

Department of Medical Microbiology, Haaglanden Medical Center, The Hague, The Netherlands.

Abnormal vaginal discharge may be caused by bacterial vaginosis, vulvovaginal candidiasis, trichomoniasis and/or aerobic vaginitis. For the development of a diagnostic algorithm, tree-based classification analysis was performed on symptoms, signs and bedside test results of 56 patients, and laboratory tests (culture, Nugent score, qPCRs) were compared. Amplicon sequencing of the 16S rRNA gene was used as reference test for bacterial vaginosis and aerobic vaginitis, culture for vulvovaginal candidiasis and qPCR for trichomoniasis. For bacterial vaginosis, the best diagnostic algorithm was to screen at the bedside with a pH and odour test and if positive, to confirm by qPCR (sensitivity 94%; specificity 97%) rather than Nugent score (sensitivity of 59%; specificity 97%; P = 0.031). The analysis for the other infections was less conclusive due to the low number of patients with these infections. For bacterial vaginosis, the developed algorithm is sensitive, specific, and reduces the need for laboratory tests in 50% of the patients.
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http://dx.doi.org/10.1016/j.diagmicrobio.2021.115431DOI Listing
September 2021

Metabolomics dissection of depression heterogeneity and related cardiometabolic risk.

Psychol Med 2021 Jun 3:1-10. Epub 2021 Jun 3.

Department of Psychiatry, Amsterdam Public Health Research Institute, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit, The Netherlands.

Background: A recent hypothesis postulates the existence of an 'immune-metabolic depression' (IMD) dimension characterized by metabolic dysregulations. Combining data on metabolomics and depressive symptoms, we aimed to identify depressions associated with an increased risk of adverse metabolic alterations.

Method: Clustering data were from 1094 individuals with major depressive disorder in the last 6 months and measures of 149 metabolites from a 1H-NMR platform and 30 depressive symptoms (IDS-SR30). Canonical correlation analyses (CCA) were used to identify main independent metabolite-symptom axes of variance. Then, for the replication, we examined the association of the identified dimensions with metabolites from the same platform and cardiometabolic diseases in an independent population-based cohort (n = 6572).

Results: CCA identified an overall depression dimension and a dimension resembling IMD, in which symptoms such as sleeping too much, increased appetite, and low energy level had higher relative loading. In the independent sample, the overall depression dimension was associated with lower cardiometabolic risk, such as (i.e. per s.d.) HOMA-1B -0.06 (95% CI -0.09 - -0.04), and visceral adipose tissue -0.10 cm2 (95% CI -0.14 - -0.07). In contrast, the IMD dimension was associated with well-known cardiometabolic diseases such as higher visceral adipose tissue 0.08 cm2 (95% CI 0.04-0.12), HOMA-1B 0.06 (95% CI 0.04-0.09), and lower HDL-cholesterol levels -0.03 mmol/L (95% CI -0.05 - -0.01).

Conclusions: Combining metabolomics and clinical symptoms we identified a replicable depression dimension associated with adverse metabolic alterations, in line with the IMD hypothesis. Patients with IMD may be at higher cardiometabolic risk and may benefit from specific treatment targeting underlying metabolic dysregulations.
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http://dx.doi.org/10.1017/S0033291721001471DOI Listing
June 2021

Andexanet Alfa or Prothrombin Complex Concentrate for Factor Xa Inhibitor Reversal in Acute Major Bleeding: A Systematic Review and Meta-Analysis.

Crit Care Med 2021 10;49(10):e1025-e1036

Department of Trauma Surgery, Leiden University Medical Center, Leiden, The Netherlands.

Objectives: To combine evidence on andexanet alfa and prothrombin complex concentrates for factor Xa inhibitor-associated bleeding to guide clinicians on reversal strategies.

Data Sources: Embase, Pubmed, Web of Science, and the Cochrane Library.

Study Selection: Observational studies and randomized clinical trials studying hemostatic effectiveness of andexanet alfa or prothrombin complex concentrate for acute reversal of factor Xa inhibitor-associated hemorrhage.

Data Extraction: Two independent reviewers extracted the data from the studies. Visualization and comparison of hemostatic effectiveness using Sarode et al or International Society of Thrombosis and Hemostasis Scientific and Standardization Committee criteria at 12 and 24 hours, (venous) thrombotic event rates, and inhospital mortality were performed by constructing Forest plots. Exploratory analysis using a logistic mixed model analysis was performed to identify factors associated with effectiveness and venous thromboembolic event.

Data Synthesis: A total of 21 studies were included (andexanet: 438 patients; prothrombin complex concentrate: 1,278 patients). The (weighted) mean effectiveness for andexanet alfa was 82% at 12 hours and 71% at 24 hours. The (weighted) mean effectiveness for prothrombin complex concentrate was 88% at 12 hours and 76% at 24 hours. The mean 30-day symptomatic venous thromboembolic event rates were 5.0% for andexanet alfa and 1.9% for prothrombin complex concentrate. The mean 30-day total thrombotic event rates for andexanet alfa and prothrombin complex concentrate were 10.7% and 3.1%, respectively. Mean inhospital mortality was 23.3% for andexanet versus 15.8% for prothrombin complex concentrate. Exploratory analysis controlling for potential confounders did not demonstrate significant differences between both reversal agents.

Conclusions: Currently, available evidence does not unequivocally support the clinical effectiveness of andexanet alfa or prothrombin complex concentrate to reverse factor Xa inhibitor-associated acute major bleeding, nor does it permit conventional meta-analysis of potential superiority. Neither reversal agent was significantly associated with increased effectiveness or a higher rate of venous thromboembolic event. These results underscore the importance of randomized controlled trials comparing the two reversal agents and may provide guidance in designing institutional guidelines.
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http://dx.doi.org/10.1097/CCM.0000000000005059DOI Listing
October 2021

Correlation or regression, that's the question.

Eur J Endocrinol 2021 May 10;184(6):E15-E18. Epub 2021 May 10.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

There are different ways to quantify the relation between two or more continuous variables. Some researchers use correlation coefficients; others will apply regression methods such as linear regression. In this paper, we show that the choice between correlation and regression is not purely a statistical one but largely depends on the research aims. Importantly, one should always inspect the data before using either of the two methods.
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http://dx.doi.org/10.1530/EJE-21-0251DOI Listing
May 2021

Glucocorticoid use and risk of first and recurrent venous thromboembolism: self-controlled case-series and cohort study.

Br J Haematol 2021 06 21;193(6):1194-1202. Epub 2021 Mar 21.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

Glucocorticoid treatment increases venous thromboembolism (VTE) risk. Whether this is due to the medication or the underlying disease, or affects the risk of VTE recurrence, has been difficult to determine. The aim of our present study was to quantify the risk for first and recurrent VTE associated with oral glucocorticoids use, considering the underlying disease. A total of 2547 patients with VTE from the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) study were linked to the Dutch Pharmaceutical Statistics register. The risk of first VTE during periods of exposure with oral glucocorticoids was estimated by the self-controlled case series method and that of recurrent VTE was examined in a cohort design. The incidence rate ratio (IRR) of first VTE in the period of glucocorticoid treatment was 3·51 [95% confidence interval (CI) 2·55-4·80]. This IRR was 2·53 (95% CI 1·10-5·72) in the week before treatment started, 5·28 (95% CI 2·89-9·53) in the first 7 days of treatment, remained elevated afterwards and decreased to 1·55 (95% CI 0·85-3·12) after 6 months, as compared to unexposed periods. The hazard ratio for recurrence was 2·72 (95% CI 1·64-4·78) in treatment periods as compared with no treatment. The increased risk of VTE associated with oral glucocorticoid treatment is due to a combined effect of the treatment and the underlying disease, remaining high during the first months of prescription.
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http://dx.doi.org/10.1111/bjh.17388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251551PMC
June 2021

Urinary oxidized, but not enzymatic vitamin E metabolites are inversely associated with measures of glucose homeostasis in middle-aged healthy individuals.

Clin Nutr 2021 06 3;40(6):4192-4200. Epub 2021 Feb 3.

Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.

Background & Aims: Damage induced by lipid peroxidation has been associated with impaired glucose homeostasis. Vitamin E (α-tocopherol, α-TOH) competitively reacts with lipid peroxyl radicals to mitigate oxidative damage, and forms oxidized vitamin E metabolites. Accordingly, we aimed to investigate the associations between α-TOH metabolites (oxidized and enzymatic) in both circulation and urine and measures of glucose homeostasis in the general middle-aged population.

Methods: This cross-sectional study was embedded in the population-based Netherlands Epidemiology of Obesity (NEO) Study. α-TOH metabolites in blood (α-TOH and α-CEHC-SO) and urine [sulfate (SO) and glucuronide (GLU) of both α-TLHQ (oxidized) and α-CEHC (enzymatic)] were quantified by liquid chromatography coupled with tandem mass spectrometry (LC/MS-MS). Measures of glucose homeostasis (HOMA-B, HOMA-IR, Insulinogenic index and Matsuda index) were obtained from fasting and postprandial blood samples. Multivariable linear regression analyses were performed to assess the associations of α-TOH metabolites and measures of glucose homeostasis.

Results: We included 498 participants (45% men) with mean (SD) age of 55.8 (6.1) years who did not use glucose-lowering medication. While blood α-TOH was not associated with measures of glucose homeostasis, urinary oxidized metabolites (α-TLHQ-SO/GLU) were associated with HOMA-IR and Matsuda index. For example, a one-SD higher α-TLHQ-SO was associated with 0.92 (95% CI: 0.87, 0.97) fold lower HOMA-IR and 1.06 (1.01, 1.11) fold higher Matsuda index, respectively. Similar results were obtained for the urinary α-TLHQ to α-CEHC ratio as a measure of oxidized-over-enzymatic conversion of α-TOH.

Conclusion: Higher urinary levels of oxidized α-TOH metabolites as well as higher oxidized-to-enzymatic α-TOH metabolite ratio, but not circulating α-TOH or enzymatic metabolites, were associated with lower insulin resistance. Rather than circulating α-TOH, estimates of the conversion of α-TOH might be informative in relation to health and disease.
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http://dx.doi.org/10.1016/j.clnu.2021.01.039DOI Listing
June 2021

Alcohol and Brain Development in Adolescents and Young Adults: A Systematic Review of the Literature and Advisory Report of the Health Council of the Netherlands.

Adv Nutr 2021 07;12(4):1379-1410

Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.

Young people, whose brains are still developing, might entail a greater vulnerability to the effects of alcohol consumption on brain function and development. A committee of experts of the Health Council of the Netherlands evaluated the state of scientific knowledge regarding the question whether alcohol negatively influences brain development in young people. A systematic literature search for prospective studies was performed in PubMed and PsychINFO, for longitudinal studies of adolescents or young adults ranging between 12 and 24 y of age at baseline, investigating the relation between alcohol use and outcome measures of brain structure and activity, cognitive functioning, educational achievement, or alcohol use disorder (AUD), with measures at baseline and follow-up of the outcome of interest. Data were extracted from original articles and study quality was assessed using the Newcastle-Ottawa Scale. A total of 77 studies were included, 31 of which were of sufficient quality in relation to the study objectives. There were indications that the gray matter of the brain develops abnormally in young people who drink alcohol. In addition, the more often young people drink or the younger they start, the higher the risk of developing AUD later in life. The evidence on white matter volume or quality, brain activity, cognitive function, and educational achievement is still limited or unclear. The committee found indications that alcohol consumption can have a negative effect on brain development in adolescents and young adults and entails a risk of later AUD. The committee therefore considers it a wise choice for adolescents and young adults not to drink alcohol.
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http://dx.doi.org/10.1093/advances/nmaa170DOI Listing
July 2021

Diet-Derived Circulating Antioxidants and Risk of Coronary Heart Disease: A Mendelian Randomization Study.

J Am Coll Cardiol 2021 01;77(1):45-54

Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Background: Previously, observational studies have identified associations between higher levels of dietary-derived antioxidants and lower risk of coronary heart disease (CHD), whereas randomized clinical trials showed no reduction in CHD risk following antioxidant supplementation.

Objectives: The purpose of this study was to investigate possible causal associations between dietary-derived circulating antioxidants and primary CHD risk using 2-sample Mendelian randomization (MR).

Methods: Single-nucleotide polymorphisms for circulating antioxidants (vitamins E and C, retinol, β-carotene, and lycopene), assessed as absolute levels and metabolites, were retrieved from the published data and were used as genetic instrumental variables. Summary statistics for gene-CHD associations were obtained from 3 databases: the CARDIoGRAMplusC4D consortium (60,801 cases; 123,504 control subjects), UK Biobank (25,306 cases; 462,011 control subjects), and FinnGen study (7,123 cases; 89,376 control subjects). For each exposure, MR analyses were performed per outcome database and were subsequently meta-analyzed.

Results: Among an analytic sample of 768,121 individuals (93,230 cases), genetically predicted circulating antioxidants were not causally associated with CHD risk. For absolute antioxidants, the odds ratio for CHD ranged between 0.94 (95% confidence interval [CI]: 0.63 to 1.41) for retinol and 1.03 (95% CI: 0.97 to 1.10) for β-carotene per unit increase in ln-transformed antioxidant values. For metabolites, the odds ratio ranged between 0.93 (95% CI: 0.82 to 1.06) for γ-tocopherol and 1.01 (95% CI: 0.95 to 1.08) for ascorbate per 10-fold increase in metabolite levels.

Conclusions: Evidence from our study did not support a protective effect of genetic predisposition to high dietary-derived antioxidant levels on CHD risk. Therefore, it is unlikely that taking antioxidants to increase blood antioxidants levels will have a clinical benefit for the prevention of primary CHD.
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http://dx.doi.org/10.1016/j.jacc.2020.10.048DOI Listing
January 2021

Increasing levels of von Willebrand factor and factor VIII with age in patients affected by von Willebrand disease: REPLY from original authors Biguzzi et al.

J Thromb Haemost 2021 01;19(1):310

A. Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1111/jth.15150DOI Listing
January 2021

Mediation of the association between obesity and osteoarthritis by blood pressure, vessel wall stiffness and subclinical atherosclerosis.

Rheumatology (Oxford) 2021 07;60(7):3268-3277

Department of Rheumatology.

Objective: We investigated the role of blood pressure, vessel wall stiffness [pulse wave velocity (PWV)] and subclinical atherosclerosis markers [carotid intima-media thickness (cIMT), popliteal vessel wall thickness (pVWT)] as mediators of the association of obesity with OA.

Methods: We used cross-sectional data from a subset of the population-based NEO study (n = 6334). We classified clinical hand and knee OA by the ACR criteria, and structural knee OA, effusion and bone marrow lesions on MRI (n = 1285). cIMT was assessed with ultrasonography. pVWT was estimated on knee MRI (n = 1285), and PWV by abdominal velocity-encoded MRIs (n = 2580), in subpopulations. Associations between BMI and OA were assessed with logistic regression analyses, adjusted for age, sex and education. Blood pressure, cIMT, pVWT and PWV were added to the model to estimate mediation.

Results: The population consisted of 55% women, with a mean (s.d.) age of 56(6) years. Clinical hand OA was present in 8%, clinical knee OA in 10%, and structural knee OA in 12% of participants. BMI was positively associated with all OA outcomes. cIMT partially mediated the association of BMI with clinical hand OA [10.6 (6.2; 30.5)%], structural knee OA [3.1 (1.9; 7.3)%] and effusion [10.8 (6.0; 37.6)%]. Diastolic blood pressure [2.1 (1.6; 3.0)%] minimally mediated the association between BMI and clinical knee OA. PWV and pVWT did not mediate the association between BMI and OA.

Conclusions: cIMT and diastolic blood pressure minimally mediated the association of BMI with OA. This suggests that such mediation is trivial in the middle-aged population.
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http://dx.doi.org/10.1093/rheumatology/keaa778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516511PMC
July 2021

Perinatal death in a term fetal growth restriction randomized controlled trial: the paradox of prior risk and consent.

Am J Obstet Gynecol MFM 2020 11 24;2(4):100239. Epub 2020 Sep 24.

Leiden University Medical Center, Leiden, the Netherlands.

Background: The disproportionate intrauterine growth intervention trial at term was an intention to treat analysis and compared labor induction with expectant monitoring in pregnancies complicated by fetal growth restriction at term and showed equivalence for neonatal outcomes.

Objective: To evaluate trial participation bias and to examine the generalizability of the results of an obstetrical randomized trial.

Study Design: We used data from participants and nonparticipants of a randomized controlled trial-the disproportionate intrauterine growth intervention trial at term (n=1116) -to perform a secondary analysis. This study compared induction of labor and expectant management in women with term growth restriction. Data were collected in the same manner for both groups. Baseline characteristics and neonatal and maternal outcomes were compared. The primary outcome was a composite measure of adverse neonatal outcome. Secondary outcomes were delivery by cesarean delivery and instrumental vaginal delivery; length of stay in the neonatal intensive care, neonatal ward, and the maternal hospital; and maternal morbidity.

Results: Nonparticipants were older, had a lower body mass index, had a higher level of education, smoked less, and preferred expectant management. The time between study inclusion and labor onset was shorter in participants than in nonparticipants. Notably, 4 perinatal deaths occurred among nonparticipants and none among participants. Among nonparticipants, there were more children born with a birthweight below the third centile. The nonparticipants who had expectant management were monitored less frequently than the participants in both the intervention and the expectant arm.

Conclusion: We found less favorable outcomes and more perinatal deaths in nonparticipants. Protocol-driven management, differences between participants and nonparticipants, or the fact that nonparticipants had a preference for expectant management might explain the findings.
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http://dx.doi.org/10.1016/j.ajogmf.2020.100239DOI Listing
November 2020

Multiple testing: when is many too much?

Eur J Endocrinol 2021 Mar;184(3):E11-E14

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

In almost all medical research, more than a single hypothesis is being tested or more than a single relation is being estimated. Testing multiple hypotheses increases the risk of drawing a false-positive conclusion. We briefly discuss this phenomenon, which is often called multiple testing. Also, methods to mitigate the risk of false-positive conclusions are discussed.
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http://dx.doi.org/10.1530/EJE-20-1375DOI Listing
March 2021

Risk and Time Pattern of Recurrences After Local Endoscopic Resection of T1 Colorectal Cancer: A Meta-analysis.

Clin Gastroenterol Hepatol 2022 Feb 1;20(2):e298-e314. Epub 2020 Dec 1.

Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.

Background & Aims: Growing numbers of patients with T1 CRC are being treated with local endoscopic resection only and as a result, the need for optimization of surveillance strategies for these patients also increases. We aimed to estimate the cumulative incidence and time pattern of CRC recurrences for endoscopically treated patients with T1 CRC.

Methods: Using a systematic literature search in PubMed, EMBASE, Web of Science and Cochrane Library (from inception till 15 May 2020), we identified and extracted data from studies describing the cumulative incidence of local or distant CRC recurrence for patients with T1 CRC treated with local endoscopic resection only. Pooled estimates were calculated using mixed-effect logistic regression models.

Results: Seventy-one studies with 5167 unique, endoscopically treated patients with T1 CRC were included. The pooled cumulative incidence of any CRC recurrence was 3.3% (209 events; 95% CI, 2.6%-4.3%; I = 54.9%), with local and distant recurrences being found at comparable rates (pooled incidences 1.9% and 1.6%, respectively). CRC-related mortality was observed in 42 out of 2519 patients (35 studies; pooled incidence 1.7%, 95% CI, 1.2%-2.2%; I = 0%), and the CRC-related mortality rate among patients with recurrence was 40.8% (42/103 patients). The vast majority of recurrences (95.6%) occurred within 72 months of follow-up. Pooled incidences of any CRC recurrence were 7.0% for high-risk T1 CRCs (28 studies; 95% CI, 4.9%-9.9%; I = 48.1%) and 0.7% (36 studies; 95% CI, 0.4%-1.2%; I = 0%) for low-risk T1 CRCs.

Conclusions: Our meta-analysis provides quantitative outcome measures which are relevant to guidelines on surveillance after local endoscopic resection of T1 CRC.
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http://dx.doi.org/10.1016/j.cgh.2020.11.032DOI Listing
February 2022

A Workflow for Missing Values Imputation of Untargeted Metabolomics Data.

Metabolites 2020 Nov 26;10(12). Epub 2020 Nov 26.

Department of Clinical Epidemiology, Leiden University Medical Center, Postal Zone C7-P, PO Box 9600, 2300 RC Leiden, The Netherlands.

Metabolomics studies have seen a steady growth due to the development and implementation of affordable and high-quality metabolomics platforms. In large metabolite panels, measurement values are frequently missing and, if neglected or sub-optimally imputed, can cause biased study results. We provided a publicly available, user-friendly script to streamline the imputation of missing endogenous, unannotated, and xenobiotic metabolites. We evaluated the multivariate imputation by chained equations (MICE) and k-nearest neighbors (kNN) analyses implemented in our script by simulations using measured metabolites data from the Netherlands Epidemiology of Obesity (NEO) study ( = 599). We simulated missing values in four unique metabolites from different pathways with different correlation structures in three sample sizes (599, 150, 50) with three missing percentages (15%, 30%, 60%), and using two missing mechanisms (completely at random and not at random). Based on the simulations, we found that for MICE, larger sample size was the primary factor decreasing bias and error. For kNN, the primary factor reducing bias and error was the metabolite correlation with its predictor metabolites. MICE provided consistently higher performance measures particularly for larger datasets ( > 50). In conclusion, we presented an imputation workflow in a publicly available script to impute untargeted metabolomics data. Our simulations provided insight into the effects of sample size, percentage missing, and correlation structure on the accuracy of the two imputation methods.
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http://dx.doi.org/10.3390/metabo10120486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761057PMC
November 2020

Mortality, life expectancy, and causes of death of persons with hemophilia in the Netherlands 2001-2018.

J Thromb Haemost 2021 03 18;19(3):645-653. Epub 2020 Dec 18.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

Background: Treatment of patients with hemophilia has advanced over the past decades, but it is unknown whether this has resulted in a normal life expectancy in the Netherlands.

Objective: This observational cohort study aimed to assess all-cause and cause-specific mortality in patients with hemophilia in the Netherlands between 2001 and 2018 and to compare mortality and life expectancy with previous survival assessments from 1973 onward.

Patients/methods: All 1066 patients with hemophilia who participated in a nationwide survey in 2001 were followed until July 2018.

Results: Information on 1031 individuals (97%) was available, of whom 142 (14%) deceased during follow-up. Compared with the general Dutch male population, mortality of patients with hemophilia was still increased (standardized mortality ratio: 1.4, 95% confidence interval: 1.2-1.7). Intracranial bleeding and malignancies were the most common causes of death. Estimated median life expectancy of patients with hemophilia was 77 years, 6 years lower than the median life expectancy of the general Dutch male population (83 years). Over the past 45 years, death rates of patients with hemophilia have consistently decreased, approaching the survival experience of the general population. Over the past decades, mortality due to human immunodeficiency virus and hepatitis C virus infections has decreased, death due to intracranial hemorrhages has increased, and death due to ischemic heart disease has remained consistently low over time.

Conclusions: Survival in patients with hemophilia in the Netherlands has improved over time but is still lower than that of the general population.
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http://dx.doi.org/10.1111/jth.15182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986360PMC
March 2021

Differing time-orders of inflammation decrease between ACPA subsets in RA patients suggest differences in underlying inflammatory pathways.

Rheumatology (Oxford) 2021 06;60(6):2969-2975

Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.

Objectives: Advanced imaging modalities have shown that not only joints but also bones and tendon sheaths can be inflamed at diagnosis of RA. We aimed to better understand the time-order in which the inflamed tissues respond to DMARD treatment. Also, because ACPA status may reflect a different pathophysiology, differences in time-order of inflammation decrease were hypothesized between these disease types.

Methods: A total of 216 consecutive patients presenting with RA (n = 176) or undifferentiated arthritis (n = 40), who all started with conventional synthetic DMARD treatment, were studied. 1.5T contrast-enhanced hand and foot MRIs were performed before treatment and after 4, 12 and 24 months. Cross-lagged models evaluated the influence of two time patterns: a simultaneous pattern ('change in one inflammatory feature associated with change in another feature') and a subsequent pattern ('change in one inflammatory feature preceded change in another feature'). ACPA stratification was performed.

Results: The median symptom duration at presentation was 13 weeks. Forty-four percent of patients was ACPA-positive. All pairs of inflammatory features decreased simultaneously in all time intervals (0-4/4-12/12-24 months; P < 0.05). Moreover, time-orders were identified: synovitis decrease preceded tenosynovitis decrease (0-4 to >4-12 months; P = 0.02 and 4-12 to >12-24 months; P = 0.03). Largely similar results were obtained in both ACPA subgroups. Additionally, in ACPA-positive but not ACPA-negative patients, synovitis decrease preceded osteitis decrease (4-12 to >12-24 moths; P = 0.002).

Conclusion: This study increased the understanding of the response to treatment on the tissue level. In addition to simultaneous decrease of inflammation, synovitis decrease preceded tenosynovitis decrease. Differences in time-order of inflammation decrease between ACPA subgroups suggest differences in underlying inflammatory pathways.
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http://dx.doi.org/10.1093/rheumatology/keaa658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213431PMC
June 2021

Increasing levels of von Willebrand factor and factor VIII with age in patients affected by von Willebrand disease.

J Thromb Haemost 2021 01 23;19(1):96-106. Epub 2020 Oct 23.

A. Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Essentials VWF and FVIII increase with age in patients affected by VWD. VWF and FVIII increase in type 1 and in low levels of VWF patients. VWF and FVIII do not increase in type 1 Vicenza. FVIII increases in type 2 VWD patients. ABSTRACT: Background Increasing levels of von Willebrand factor (VWF) and factor VIII (FVIII:C) was associated with age in type 1 von Willebrand disease (VWD). Objectives To evaluate VWF and FVIII:C increase with age in a large group of patients with VWD and low levels of VWF, in whom levels were repeatedly measured. Methods Clinical charts from all patients evaluated at the A. Bianchi Bonomi Center between 1970 and 2018 were reviewed and data on VWF and FVIII:C collected. Patients affected by type 3, severe type 1 and 2N VWD were excluded. The repeated measurements were evaluated by linear mixed-effects models. A linear association between age and VWF/FVIII:C was shown after the age of 40 years in the linear mixed models and analyzed by calculating the regression slope coefficient (β). Results A total of 617 patients were included in the study (314 type 2, 112 type 1, 181 low VWF levels), with a median age at first measurement of 28 years (interquartile range 14/42) and a mean follow-up of 16 years (standard deviation 11). VWF and FVIII:C increased with age in the whole group. The increase became linear after the age of 40 years (3.68 and 7.44 IU/dL per decade for VWF:activity and FVIII:C). In type 2, FVIII:C increased with age, whereas an increase of both VWF:activity and FVIII:C were shown in patients with type 1 VWD and low levels of VWF. Conclusions A differential increase of VWF and FVIII:C with age was shown among in different ages and types of VWD.
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http://dx.doi.org/10.1111/jth.15116DOI Listing
January 2021

Formulating causal questions and principled statistical answers.

Stat Med 2020 12 23;39(30):4922-4948. Epub 2020 Sep 23.

Department of Statistics, Uppsala University, Uppsala, Sweden.

Although review papers on causal inference methods are now available, there is a lack of introductory overviews on what they can render and on the guiding criteria for choosing one particular method. This tutorial gives an overview in situations where an exposure of interest is set at a chosen baseline ("point exposure") and the target outcome arises at a later time point. We first phrase relevant causal questions and make a case for being specific about the possible exposure levels involved and the populations for which the question is relevant. Using the potential outcomes framework, we describe principled definitions of causal effects and of estimation approaches classified according to whether they invoke the no unmeasured confounding assumption (including outcome regression and propensity score-based methods) or an instrumental variable with added assumptions. We mainly focus on continuous outcomes and causal average treatment effects. We discuss interpretation, challenges, and potential pitfalls and illustrate application using a "simulation learner," that mimics the effect of various breastfeeding interventions on a child's later development. This involves a typical simulation component with generated exposure, covariate, and outcome data inspired by a randomized intervention study. The simulation learner further generates various (linked) exposure types with a set of possible values per observation unit, from which observed as well as potential outcome data are generated. It thus provides true values of several causal effects. R code for data generation and analysis is available on www.ofcaus.org, where SAS and Stata code for analysis is also provided.
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http://dx.doi.org/10.1002/sim.8741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756489PMC
December 2020

Meta-analysis of continuous outcomes: Using pseudo IPD created from aggregate data to adjust for baseline imbalance and assess treatment-by-baseline modification.

Res Synth Methods 2020 Nov 25;11(6):780-794. Epub 2020 Jul 25.

Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

Meta-analysis of individual participant data (IPD) is considered the "gold-standard" for synthesizing clinical study evidence. However, gaining access to IPD can be a laborious task (if possible at all) and in practice only summary (aggregate) data are commonly available. In this work we focus on meta-analytic approaches of comparative studies where aggregate data are available for continuous outcomes measured at baseline (pre-treatment) and follow-up (post-treatment). We propose a method for constructing pseudo individual baselines and outcomes based on the aggregate data. These pseudo IPD can be subsequently analysed using standard analysis of covariance (ANCOVA) methods. Pseudo IPD for continuous outcomes reported at two timepoints can be generated using the sufficient statistics of an ANCOVA model, i.e., the mean and standard deviation at baseline and follow-up per group, together with the correlation of the baseline and follow-up measurements. Applying the ANCOVA approach, which crucially adjusts for baseline imbalances and accounts for the correlation between baseline and change scores, to the pseudo IPD, results in identical estimates to the ones obtained by an ANCOVA on the true IPD. In addition, an interaction term between baseline and treatment effect can be added. There are several modeling options available under this approach, which makes it very flexible. Methods are exemplified using reported data of a previously published IPD meta-analysis of 10 trials investigating the effect of antihypertensive treatments on systolic blood pressure, leading to identical results compared with the true IPD analysis and of a meta-analysis of fewer trials, where baseline imbalance occurred.
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http://dx.doi.org/10.1002/jrsm.1434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754323PMC
November 2020
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