Acromegaly is a rare disease and thus challenging to accurately quantify epidemiologically. In this comprehensive literature review, we compare different approaches to studying acromegaly from an... Show moreAcromegaly is a rare disease and thus challenging to accurately quantify epidemiologically. In this comprehensive literature review, we compare different approaches to studying acromegaly from an epidemiological perspective and describe the temporal evolution of the disease pertaining to epidemiological variables, clinical presentation and mortality. We present updated epidemiological data from the population-based Danish cohort of patients with acromegaly (AcroDEN), along with meta-analyses of existing estimates from around the world.Based on this, we conclude that the incidence, prevalence and age at acromegaly diagnosis are all steadily increasing, but with considerable variation between studies. An increased number of incidental cases may contribute to the increase in incidence and age at diagnosis, respectively. The clinical features at presentation are trending toward a milder disease phenotype at diagnosis, and advances in therapeutic options have reduced the mortality of patients with acromegaly to a level similar to that of the general population. Moreover, the underlying cause of death has shifted from cardiovascular to malignant neoplastic diseases. Show less
Aymon, R.; Mongin, D.; Bergstra, S.A.; Choquette, D.; Codreanu, C.; Cock, D. de; ... ; Lauper, K. 2023
Background In a clinical trial setting, patients with rheumatoid arthritis (RA) taking the Janus kinase inhibitor (JAKi) tofacitinib demonstrated higher adverse events rates compared with those... Show moreBackground In a clinical trial setting, patients with rheumatoid arthritis (RA) taking the Janus kinase inhibitor (JAKi) tofacitinib demonstrated higher adverse events rates compared with those taking the tumour necrosis factor inhibitors (TNFi) adalimumab or etanercept.Objective Compare treatment discontinuations for adverse events (AEs) among second-line therapies in an international real-world RA population.Methods Patients initiating JAKi, TNFi or a biological with another mode of action (OMA) from 17 registers participating in the ‘JAK-pot’ collaboration were included. The primary outcome was the rate of treatment discontinuation due to AEs. We used unadjusted and adjusted cause-specific Cox proportional hazard models to compare treatment discontinuations for AEs among treatment groups by class, but also evaluating separately the specific type of JAKi.Results Of the 46 913 treatment courses included, 12 523 were JAKi (43% baricitinib, 40% tofacitinib, 15% upadacitinib, 2% filgotinib), 23 391 TNFi and 10 999 OMA. The adjusted cause-specific hazard rate of treatment discontinuation for AEs was similar for TNFi versus JAKi (1.00, 95% CI 0.92 to 1.10) and higher for OMA versus JAKi (1.11, 95% CI 1.01 to 1.23), lower with TNFi compared with tofacitinib (0.81, 95% CI 0.71 to 0.90), but higher for TNFi versus baricitinib (1.15, 95% CI 1.01 to 1.30) and lower for TNFi versus JAKi in patients 65 or older with at least one cardiovascular risk factor (0.79, 95% CI 0.65 to 0.97).Conclusion While JAKi overall were not associated with more treatment discontinuations for AEs, subgroup analyses suggest varying patterns with specific JAKi, such as tofacitinib, compared with TNFi. However, these observations should be interpreted cautiously, given the observational study design. Show less
Redeker, I.; Landewé, R.; Heijde, D. van der; Ramiro, S.; Boonen, A.; Dougados, M.; ... ; Kiltz, U. 2023
ObjectiveThe objective of this study is to build a structural model visualising and quantifying the interrelationships of different disease outcomes with the Assessment of SpondyloArthritis... Show moreObjectiveThe objective of this study is to build a structural model visualising and quantifying the interrelationships of different disease outcomes with the Assessment of SpondyloArthritis International Society Health Index (ASAS HI) in patients with axial spondyloarthritis (axSpA).MethodsCross-sectional data collected at month 72 of the Devenir des Spondylarthropathies Indifferenciees Recentes cohort was analysed. Combining prior knowledge and observed data, probabilistic Bayesian network modelling was used to study how the interplay of different disease outcomes affects the ASAS HI, which measures disease-specific overall functioning and health. Disease outcomes comprised, among others, the Ankylosing Spondylitis (AS) Disease Activity Score (ASDAS) and the Bath AS Functional Index (BASFI).ResultsData of 384 patients were analysed. The obtained structure suggests that ASAS HI is determined by both patient-reported physical function (BASFI) and disease activity (ASDAS). The parameters of the structural model show that an increase of ASDAS or BASFI by 1 unit corresponds to an increase of ASAS HI by 0.70 or 1.25 units, respectively. Moreover, the model suggests that disease activity has an indirect impact on ASAS HI via BASFI. No relationship between spinal mobility or structural damage and ASAS HI was found.ConclusionsThis is the first structural model developed to better understand the construct and the interplay between clinically relevant outcomes related to ASAS HI in axSpA patients. It shows that disease activity and physical function have a strong impact on ASAS HI, confirming it to be a valid construct of overall functioning and health in axSpA patients. Show less
Heckert, S.L.; Maassen, J.M.; Cessie, S. le; Goekoop-Ruiterman, Y.P.M.; Güler-Yüksel, M.; Lems, W.; ... ; Allaart, C.F. 2023
Objectives To study long-term (up to 20-year) mortality of two treat-to-target trial cohorts in undifferentiated arthritis (UA) and early rheumatoid arthritis (RA).Methods The BeSt ... Show moreObjectives To study long-term (up to 20-year) mortality of two treat-to-target trial cohorts in undifferentiated arthritis (UA) and early rheumatoid arthritis (RA).Methods The BeSt (BehandelStrategieen) study (n=508, early RA) was performed between 2000 and 2012. For 10 years, patients were treated-to-target disease activity score (DAS)<= 2.4.The Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED) study (n=610, early RA/UA) was performed between 2007 and 2015. For 5 years, patients were treated-to-target DAS<1.6.Vital status of BeSt/IMPROVED participants was assessed up to and including 31 December 2021. Standardised mortality ratios (SMRs) were calculated. Stratified analyses for anticitrullinated protein antibody (ACPA) and smoking status were performed. Death causes and the potential effect of disease activity during the trial period on late mortality were assessed.Results Excess mortality was found in both BeSt (SMR 1.32, 95% CI 1.14 to 1.53) and IMPROVED (SMR 1.33, 95% CI 1.10 to 1.63) and became manifest after 10 years. Excess mortality was statistically significant in ACPA+ patients who smoked (BeSt: SMR 2.80, 95% CI 2.16 to 3.64; IMPROVED: 2.14, 95% CI 1.33 to 3.45). Mean survival time was 10 (95% CI 5 to 16) months shorter than expected in BeSt and 13 (95% CI 11 to 16) months in IMPROVED. The HR for mortality was 1.34 (95% CI 0.96 to 1.86; BeSt)/1.13 (95% CI 0.67 to 1.91; IMPROVED) per 1 point increase in mean DAS during the trial. The main cause of death was malignancy.Conclusions After long-term treatment-to-target, excess mortality occurred in patients with RA after>10 years since treatment start, with smoking as an important risk factor. Show less
Anijs, R.J.S.; Chen, Q.; Hulle, T. van der; Versteeg, H.H.; Klok, F.A.; Lijfering, W.M.; Cannegieter, S.C. 2023
Background: Colorectal cancer (CRC) is the third most prevalent cancer type. CRC-patients are at increased risk of venous and arterial thromboembolism (TE), but the magnitude of the risks, their... Show moreBackground: Colorectal cancer (CRC) is the third most prevalent cancer type. CRC-patients are at increased risk of venous and arterial thromboembolism (TE), but the magnitude of the risks, their predictors and consequences are not exactly known.Objectives: We aimed to determine incidence, predictors and prognosis of TE after incident CRC in a large, unselected population. Methods: Using data from Statistics Netherlands and the Netherlands Comprehensive Cancer Organization, all incident CRC-patients were identified between 2013 and 2018 plus a sample of 1:2 age- and sex-matched control subjects. Incidence rates and cumulative incidences for TE were estimated. Predictor variables for TE were explored by univariable Cox regression. The association between TE and all-cause mortality was evaluated by multivariable time-dependent Cox regression.Results: 68,238 incident CRC-patients were matched to 136,476 controls. CRC-patients had a 1-year cumulative venous TE (VTE) incidence of 1.93 % (95%CI 1.83-2.04), versus 0.24 % (95%CI 0.21-0.27) in controls (HR 8.85; 95%CI 7.83-9.99). For arterial TE (ATE), this was 2.74 % (95%CI 2.62-2.87) in CRC versus 1.88 % (95%CI 1.81-1.95) in controls (HR 1.57; 95%CI 1.47-1.66). Cancer stage, surgery, chemotherapy and asthma were predictors for VTE, whereas age, prior ATE and Parkinson's disease were predictors for ATE. CRC patients with TE had an increased risk of all-cause mortality (VTE HR; 3.68 (95%CI 3.30-4.10, ATE HR; 3.05 (95%CI 2.75-3.39)) compared with CRC-patients without TE.Conclusions: This Dutch nationwide cohort study adds detailed knowledge on the risk of VTE and ATE, their predictors and prognosis in CRC-patients. These findings may drive TE prophylactic management decisions. Show less
This thesis addresses potential threats to the validity of observational epidemiological studies. Examples of these potential sources of bias are confounding, missing data, selection bias, and... Show moreThis thesis addresses potential threats to the validity of observational epidemiological studies. Examples of these potential sources of bias are confounding, missing data, selection bias, and measurement error. Although various methods have been developed to mitigate these biases, it is often unclear which methods can be used in which empirical settings. It is also common that issues discussed in methodological studies are overlooked in clinical research. Thus, we investigated problems ofmissing data, selection bias, and measurement error occurring in several specific observational settings and discuss how to optimally handle them. Show less
BackgroundPrevious studies have proposed different formulas of estimating glomerular filtration rate (eGFR) among clinical patients. The comprehensive comparison of eGFR formulas is not well... Show moreBackgroundPrevious studies have proposed different formulas of estimating glomerular filtration rate (eGFR) among clinical patients. The comprehensive comparison of eGFR formulas is not well established in a Japanese population. We compared eGFR values and chronic kidney disease (CKD) classification of nine different eGFR in a Japanese general population sample.MethodsWe analyzed 469 Japanese community-dwelling adults (184 men) without any self-reported kidney disease. GFR estimated using the 4- and 6-parameter Modification of Diet in Renal Disease (MDRD) formulas (MDRD4 and MDRD6); the CKD-EPI formulas based on creatinine with (CKD-EPI-2009) and without race coefficient (CKD-EPI-2021), on cystatin C (CKD-EPI-Cys), on both (CKD-EPI-CreCys); the Japanese creatinine-based formula (JPN-Cre), cystatin C-based formula (JPN-Cys), and modified CKD-EPI formula (JPN-CKD-EPI). CKD stages were defined by KDIGO guidelines (eGFR < 60 ml/min/1.73 m2).ResultseGFRJPN-Cre (mean = 71.2; SD = 14.3) were much lower than eGFRCKD-EPI-2021 (mean = 94.2; SD = 12.7), while eGFRJPN-Cys (mean = 102.8; SD = 24.2) was comparable to the MDRD and CKD-EPI formulas. The difference between eGFRCKD-EPI-2021 and eGFRJPN-Cre showed a V-shaped distribution across eGFR levels, indicating complex errors between these formulas. We observed very low agreement in CKD classification between eGFRJPN-Cre and the eGFRCKD-EPI-2021 (kappa = 0.13; 95% confidence interval: 0.06, 0.23).ConclusionsJPN-Cre was substantially different from the CKD-EPI formula without race term (CKD-EPI-2021), which means that it is impossible to recalibrate those with a simple coefficient. Although a comparison with measured GFR should be necessary, choice of the estimation method needs caution in clinical decision-making and academic research. Show less
Spek, L. van der; Sanglier, S.; Mabeya, H.M.; Akker, T. van den; Mertens, P.L.J.M.; Houweling, T.A.J. 2020
Background Caesarean section (C-section) rates are often low among the poor and very high among the better-off in low- and middle-income countries. We examined to what extent these differences are... Show moreBackground Caesarean section (C-section) rates are often low among the poor and very high among the better-off in low- and middle-income countries. We examined to what extent these differences are explained by medical need in an African context. Methods We analyzed electronic records of 12,209 women who gave birth in a teaching hospital in Kenya in 2014. C-section rates were calculated by socioeconomic position (SEP), using maternal occupation (professional, small business, housewife, student) as indicator. We assessed if women had documented clinical indications according to hospital guidelines and if socioeconomic differences in C-section rates were explained by indication. Results Indication for C-section according to hospital guidelines was more prevalent among professionals than housewives (16% vs. 9% of all births). The C-section rate was also higher among professionals than housewives (21.1% vs. 15.8% [OR 1.43; 95%CI 1.23-1.65]). This C-section rate difference was largely explained by indication (4.7 of the 5.3 percentage point difference between professionals and housewives concerned indicated C-sections, often with previous C-section as indication). Repeat C-sections were near-universal (99%). 43% of primary C-sections had no documented indication. Over-use was somewhat higher among professionals than housewives (C-section rate among women without indication: 6.6 and 5.5% respectively), which partly explained socioeconomic differences in primary C-section rate. Conclusions Socioeconomic differences in C-section rates can be largely explained by unnecessary primary C-sections and higher supposed need due to previous C-section. Prevention of unnecessary primary C-sections and promoting safe trial of labor should be priorities in addressing C-section over-use and reducing inequalities. Tweetable abstract Unnecessary primary C-sections and ubiquitous repeat C-sections drive overall C-section rates and C-section inequalities. Show less
The research provides insight into disease behavior in both rural and semi-urban areas in Serengeti in Tanzania. It focuses on the motives and behaviors that patients exhibit when relying on local... Show moreThe research provides insight into disease behavior in both rural and semi-urban areas in Serengeti in Tanzania. It focuses on the motives and behaviors that patients exhibit when relying on local healthcare systems, classified as traditional, transitional or modern. It describes the availability, accessibility and patterns of use of these healthcare systems, in particular how they are embedded in the local cultural heritage. It shows that behavioral patterns are dominated by psycho-social and cultural factors. In addition, background characteristics, intervening factors and situation-dependent factors that influence usage patterns are described, analyzed and explained. The analytical model based on the school of "Ethnoscience" shows where the use of these medical systems is related to the historical, cultural and economic factors that determine the daily lives of the inhabitants. The analysis of the research data provides recommendations for education and training of local middle management staff in support of integrated transcultural public health policy, as initiated by the local government of Serengeti in collaboration with the local training institutions. The findings are used as input for the intended master course in Transcultural Public Health Management in the area, and elsewhere in similar circumstances. Special attention is paid to the local medical knowledge, beliefs and practices of the target population to improve public health. Show less
Inferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications.... Show moreInferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 +/- 0.137, while external model validation in an independent population-based cohort (N = 1608) achieved an AUC of 0.911. These 13 CpGs also provided accurate inference of current (average AUC(crossvalidation) 0.925 +/- 0.021, AUC(externalvalidation)0.914), former (0.766 +/- 0.023, 0.699) and never smoking (0.830 +/- 0.019, 0.781) status, allowed inferring pack-years in current smokers (10 pack-years 0.800 +/- 0.068, 0.796; 15 pack-years 0.767 +/- 0.102, 0.752) and inferring smoking cessation time in former smokers (5 years 0.774 +/- 0.024, 0.760; 10 years 0.766 +/- 0.033, 0.764; 15 years 0.767 +/- 0.020, 0.754). Model application to children revealed highly accurate inference of the true non- smoking status (6 years of age: accuracy 0.994, N = 355; 10 years: 0.994, N = 309), suggesting prenatal and passive smoking exposure having no impact on model applications in adults. The finite set of DNA methylation markers allow accurate inference of smoking habit, with comparable accuracy as plasma cotinine use, and smoking history from blood, which we envision becoming useful in epidemiology and public health research, and in medical and forensic applications. Show less
Structural brain markers are studied extensively in the field of neurodegeneration, but are thought to occur rather late in the process. Functional measures such as functional connectivity are... Show moreStructural brain markers are studied extensively in the field of neurodegeneration, but are thought to occur rather late in the process. Functional measures such as functional connectivity are gaining interest as potentially more subtle markers of neurodegeneration. However, brain structure and function are also affected by ‘normal’ brain ageing. More information is needed on how functional connectivity relates to aging, particularly in the absence of overt neurodegenerative disease. We investigated the association of age with resting-state functional connectivity in 2878 non-demented persons between 50 and 95 years of age (54.1% women) from the population-based Rotterdam Study. We obtained nine well-known resting state networks using data-driven methodology. Within the anterior default mode network, ventral attention network, and sensorimotor network, functional connectivity was significantly lower with older age. In contrast, functional connectivity was higher with older age within the visual network. Between resting state networks, we found patterns of both increases and decreases in connectivity in approximate equal proportions. Our results reinforce the notion that the aging brain undergoes a reorganization process, and serves as a solid basis for exploring functional connectivity as a preclinical marker of neurodegenerative disease. Show less
Although recent work has begun to establish that early modern plagues had selective mortality effects, it was generally accepted that the initial outbreak of Black Death in 1347-52 was a ... Show moreAlthough recent work has begun to establish that early modern plagues had selective mortality effects, it was generally accepted that the initial outbreak of Black Death in 1347-52 was a ‘universal killer’. Recent bioarchaeological work, however, has argued that the Black Death was also selective with regard to age and pre-plague health status. The issue of the Black Death’s potential sex selectivity is less clear. Bioarchaeological research hypothesizes that sex-selection in mortality was possible during the initial Black Death outbreak, and we present evidence from historical sources to test this notion. Show less
Secondary prevention of recurrent venous can be achieved in two ways, either by elimination of modifiable risk factors or by extending the anticoagulant treatment period in patients at high risk... Show moreSecondary prevention of recurrent venous can be achieved in two ways, either by elimination of modifiable risk factors or by extending the anticoagulant treatment period in patients at high risk of recurrence. The aim of this thesis was to identify modifiable risk factors for as well as factors that might be able to predict recurrent venous thrombotic events. This thesis reports on an increased risk of recurrences in women who continue or start using hormonal contraceptives after a first venous thrombotic event, suggesting that refraining from this modifiable risk factor decreases the risk of recurrence. Furthermore, this thesis describes several factors, male sex, unprovoked first event, levels of coagulation factor VIII and antibiotic use to be associated with recurrent venous thrombosis. These factors should eventually be taken together and used to build a prognostic model, which will be able to predict recurrences at a refined and individual level. Show less
The pathogenesis of OA is largely unknown; however, several risk factors are known to contribute to disease development. Treatment modalities are currently limited to alleviation of symptoms. In... Show moreThe pathogenesis of OA is largely unknown; however, several risk factors are known to contribute to disease development. Treatment modalities are currently limited to alleviation of symptoms. In order to develop better treatment modalities, increase of the understanding of the underlying mechanisms leading to OA development may provide targets for disease modification. Furthermore, knowledge regarding appropriate outcome measures that can be applied in OA research has to be increased for adequate assessment of potential treatment effects. Therefore, part I of this thesis describes studies aiming to increase the understanding of mechanisms underlying the association between known risk factors and OA, especially focussing on obesity in relation to OA in weight-bearing and non-weight-bearing joints. Furthermore, it was investigated which specific structural abnormalities on specific locations within the knee joint could best discriminate presence of symptomatic OA, and impact of knee OA and its modifiable or preventable risk on health-related quality of life was evaluated. Part II of this thesis describes two systematic reviews, assessing available instruments for measurement of the domains pain, physical function, patient global assessment and imaging in hand OA in order to enable recommendations for use in clinical trials. Show less
This thesis investigates the validity and usefulness of physician's preference-based instrumental variable analysis in clinical epidemiological studies. Chapter 2 describes a survey amongst general... Show moreThis thesis investigates the validity and usefulness of physician's preference-based instrumental variable analysis in clinical epidemiological studies. Chapter 2 describes a survey amongst general practitioners, showing substantial variation in prescribing preference and showing prescribing patterns which suggest the stochastic monotonicity assumption may be plausible for physician's preference as an instrumental variable. Chapter 3 describes an application of physician's preference-based instrumental variable analysis in a moderate-sized study, showing uninformatively wide confidence intervals which limit the usefulness of instrumental variable analysis in this setting. Chapter 4 focuses on the bias-variance trade-off of instrumental variable analysis in comparison to conventional analyses, using simulations and theoretical derivations. Chapter 5 compares instrumental variable and conventional estimates of the effect of third versus second generation oral contraceptives on occurrence of venous thromboembolism. The similarity of these estimates under different sets of assumptions suggests major confounding is unlikely. Chapter 6 contains a suggestion for an additional step for reporting of instrumental variable analyses. The focus shifts to Mendelian randomisation in the second part of the thesis. Chapter 7 reviews the methodological approaches used in Mendelian randomisation studies and the quality of reporting. Chapter 8 shows that collider-stratification bias may exist in Mendelian randomisation studies in elderly populations. Show less
This thesis aimed to identify possible risks associated with erythropoiesis-simulating agent (ESA) use. First, trends in anemia management are described, showing less ESA use in Swedish patients... Show moreThis thesis aimed to identify possible risks associated with erythropoiesis-simulating agent (ESA) use. First, trends in anemia management are described, showing less ESA use in Swedish patients with chronic kidney disease (CKD) and less ESA-treated patients had a hemoglobin above 12 g/dL. Furthermore it is shown that ESA- treated pre-dialysis patients in the Netherlands received more antihypertensive agents than patients without ESA, confirming the hypertensive effect of ESA. However, no relevant difference in routinely measured blood pressure was observed between patients with and without ESA treatment, thus the hypertensive effect of ESAs could be controlled in clinical practice. In addition, no excess of thrombotic events was shown in ESA-treated dialysis patients compared to patients without ESA treatment. In contrast, a higher risk of cardiovascular events with ESA use was indicated in Danish patients with multiple myeloma and myelodyslastic syndrome. Also, with two analytical approaches, a harmful effect of high ESA doses on mortality was indicated in Dutch dialysis patients. Last, it was shown that ESA resistance was associated with mortality in both hemodialysis and peritoneal dialysis patients. To conclude, treatment with high ESA doses was associated with a higher risk of mortality, but the mechanism is largely unknown. Show less
