Background: Donor-characteristics and donor characteristics-based decision algorithms are being progressively used in the decision process whether or not to accept an available donor kidney graft... Show moreBackground: Donor-characteristics and donor characteristics-based decision algorithms are being progressively used in the decision process whether or not to accept an available donor kidney graft for transplantation. While this may improve outcomes, the performance characteristics of the algorithms remains moderate. To estimate the impact of donor factors of grafts accepted for transplantation on transplant outcomes, and to test whether implementation of donor-characteristics-based algorithms in clinical decision-making is justified, we applied an instrumental variable analysis to outcomes for kidney donor pairs transplanted in different individuals. Methods: This analysis used (dis)congruent outcomes of kidney donor pairs as an instrument and was based on national transplantation registry data for all donor kidney pairs transplanted in separate individuals in the Netherlands (1990-2018, 2,845 donor pairs), and the United Kingdom (UK, 2000-2018, 11,450 pairs). Incident early graft loss (EGL) was used as the primary discriminatory factor. It was reasoned that a scenario with a dominant impact of donor variables on transplantation outcomes would result in high concordance of EGL in both recipients, whilst dominance of asymmetrical outcomes could indicate a more complex scenario, involving an interaction of donor, procedural and recipient factors. Findings: Incidences of congruent EGL (Netherlands: 1.2%, UK: 0.7%) were slightly lower than the arithmetical (stochastic) incidences, suggesting that once a graft has been accepted for transplantation, donor factors minimally contribute to incident EGL. A long-term impact of donor factors was explored by comparing outcomes for functional grafts from donor pairs with asymmetrical vs. symmetrical outcomes. Recipient survival was similar for both groups, but a slightly compromised graft survival was observed for grafts with asymmetrical outcomes in the UK cohort: (10 years Hazard Ratio for graft loss: 1.18 [1.03-1.35] p < 0.018); and 5 years eGFR (48.6 [48.3-49.0] vs. 46.0 [44.5-47.6] ml/min in the symmetrical outcome group, p < 0.001). Interpretation: Our results suggest that donor factors for kidney grafts deemed acceptable for transplantation impact minimally on transplantation outcomes. A strong reliance on donor factors and/or donor-characteristics-based decision algorithms could result in unjustified rejection of grafts. Future efforts to optimize transplant outcomes should focus on a better understanding of the recipient factors underlying transplant outcomes. Copyright (c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Show less
Objective: Prediction models for cardiovascular disease (CVD) mortality come from high-income countries, comprising laboratory measurements, not suitable for resource-limited countries. This study... Show moreObjective: Prediction models for cardiovascular disease (CVD) mortality come from high-income countries, comprising laboratory measurements, not suitable for resource-limited countries. This study aims to develop and validate a non-laboratory model to predict CVD mortality in a middle-income setting. Study design and setting: We used data of population aged 40-80 years from three cohort studies: Tehran Lipid and Glucose Study (n = 5160), Isfahan Cohort Study (n = 4350), and Golestan Cohort Study (n = 45,500). Using Cox proportional hazard models, we developed prediction models for men and women, separately. Cross-validation and bootstrapping procedures were applied. The models' discrimination and calibration were assessed by concordance statistic (C-index) and calibration plot, respectively. We calculated the models' sensitivity, specificity and net benefit fraction in a threshold probability of 5%. Results: The 10-year CVD mortality risks were 5.1% (95%CI: 4.8-5.5) in men and 3.1% (95%CI: 2.9%-3.3%) in women. The optimism-corrected performance of the model was c = 0.774 in men and c = 0.798 in women. The models showed good calibration in both sexes, with a predicted-to-observed ratio of 1.07 in men and 1.09 in women. The sensitivity was 0.76 in men and 0.66 in women. The net benefit fraction was higher in men compared to women (0.46 vs. 0.35). Conclusion: A low-cost model can discriminate well between low-and high-risk individuals, and can be used for screening in low-middle income countries. (C)& nbsp;2021 Elsevier Inc. All rights reserved. Show less
Objective: To assess whether the Prediction model Risk Of Bias ASsessment Tool (PROBAST) and a shorter version of this tool can identify clinical prediction models (CPMs) that perform poorly at... Show moreObjective: To assess whether the Prediction model Risk Of Bias ASsessment Tool (PROBAST) and a shorter version of this tool can identify clinical prediction models (CPMs) that perform poorly at external validation. Study Design and Setting: We evaluated risk of bias (ROB) on 102 CPMs from the Tufts CPM Registry, comparing PROBAST to a short form consisting of six PROBAST items anticipated to best identify high ROB. We then applied the short form to all CPMs in the Registry with at least 1 validation (n = 556) and assessed the change in discrimination (dAUC) in external validation cohorts (n = 1,147). Results: PROBAST classified 98/102 CPMS as high ROB. The short form identified 96 of these 98 as high ROB (98% sensitivity), with perfect specificity. In the full CPM registry, 527 of 556 CPMs (95%) were classified as high ROB, 20 (3.6%) low ROB, and 9 (1.6%) unclear ROB. Only one model with unclear ROB was reclassified to high ROB after full PROBAST assessment of all low and unclear ROB models. Median change in discrimination was significantly smaller in low ROB models (dAUC -0.9%, IQR -6.2-4.2%) compared to high ROB models (dAUC -11.7%, IQR -33.3-2.6%; P < 0.001). Conclusion: High ROB is pervasive among published CPMs. It is associated with poor discriminative performance at validation, supporting the application of PROBAST or a shorter version in CPM reviews. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license ( http:// creativecommons.org/ licenses/ by- nc- nd/ 4.0/ ) Show less
A family history of breast cancer is one of the most important risk factors for the disease. Over the last decades many genetic loci associated with breast cancer risk have been discovered. In... Show moreA family history of breast cancer is one of the most important risk factors for the disease. Over the last decades many genetic loci associated with breast cancer risk have been discovered. In spite of this, only approximately half of the familial relative risk (FRR) for breast cancer can be explained by the currently known genetic risk factor. In this thesis we have explored the role of rare genetic variants in familial breast cancer with the help of next generation sequencing. Through this approach we have not been able to identify any novel high-risk breast cancer susceptibility alleles. Although there are likely still several extremely rare risk alleles to be discovered and the presence of high-risk alleles outside of protein-coding regions cannot be excluded, it seems presently unlikely that these will explain a substantial proportion of familial breast cancer. Both our work and that of others has suggested that most non BRCA1/2 familial breast cancer cases are likely explained by a combination of low-, and moderate-risk susceptibility alleles. Show less
Tricuspid regurgitation (TR) is a frequent and complex problem, commonly combined with left-sided heart disease, such as mitral regurgitation. Significant TR is associated with increased mortality... Show moreTricuspid regurgitation (TR) is a frequent and complex problem, commonly combined with left-sided heart disease, such as mitral regurgitation. Significant TR is associated with increased mortality if left untreated or recurrent after therapy. Tricuspid regurgitation was historically often disregarded and remained undertreated. Surgery is currently the only Class I Guideline recommended therapy for TR, in the form of annuloplasty, leaflet repair, or valve replacement. As growing experience of transcatheter therapy in structural heart disease, many dedicated transcatheter tricuspid repair or replacement devices, which mimic well-established surgical techniques, are currently under development. Nevertheless, many aspects of TR are little understood, including the disease process, surgical or interventional risk stratification, and predictors of successful therapy. The optimal treatment timing and the choice of proper surgical or interventional technique for significant TR remain to be elucidated. In this context, we aim to highlight the current evidence, underline major controversial issues in this field and present a future roadmap for TR therapy. Show less
Loymans, R.J.B.; Debray, T.P.A.; Honkoop, P.J.; Termeer, E.H.; Snoeck-Stroband, J.B.; Schermer, T.R.J.; ... ; Riet, G. ter 2018
It has been well established that underserved groups have an increased risk of cardiometabolic disease and are less likely to attend health checks. This differential uptake of health checks... Show moreIt has been well established that underserved groups have an increased risk of cardiometabolic disease and are less likely to attend health checks. This differential uptake of health checks leads to suboptimal health gains from cardiometabolic screening and contributes to the widening of health inequalities in society. The cost-effectiveness of the Dutch cardiometabolic health check is still under study, but with the knowledge we already have it seems advisable to focus primarily on the underserved groups, as they have the most to gain from systematic screening. The findings described in this thesis provide strategies to optimize uptake and may be used to design future studies on this topic. In the general discussion we also advocate that the Government should invest in population-based prevention and move away from the trend of taking own responsibility as this may provide underserved groups the best possible opportunities for a healthy life(style). Show less
