Diagnostic tests are performed for various reasons. Testing has both positive and negative effects on patient outcome. The main effects are indirect, mediated through treatment decisions and their... Show moreDiagnostic tests are performed for various reasons. Testing has both positive and negative effects on patient outcome. The main effects are indirect, mediated through treatment decisions and their impact on patient outcome. To base test decisions on expected net benefit, it is important to estimate or measure those effects in a structured manner. Positive and negative effects vary over the different stakeholders in test decisions: the healthcare provider, patient and society. While testing in a situation with low pre-test probability for a certain condition can be highly valued by patients, the associated costs of testing, with limited effect on patient outcome, diverts resources from societal areas with higher benefit. In this thesis we quantified the benefit of testing across different aspects of value of diagnostic information using a pediatric example, and provided argumentation and guidance for structured evaluation of existing screening programs. We explored practice variation in pediatric testing and interviewed pediatricians to elucidate their considerations in test decisions. The general discussion provides guidance on how to increase the efficiency and thus quality of testing through both system-level interventions and interventions directed at individual providers and patients. We argue that limiting testing in diagnostic situations with a (very) low pre-test probability is equally important as a structured evaluation of test consequences for efficient use of public resources. Show less
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many inborn errors of immunity, metabolism, and hematopoiesis. No predictive models are available for these... Show moreAllogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many inborn errors of immunity, metabolism, and hematopoiesis. No predictive models are available for these disorders. We created a machine learning model using XGBoost to predict survival after HSCT using European Society for Blood and Marrow Transplant registry data of 10,888 patients who underwent HSCT for inborn errors between 2006 and 2018, and compared it to a simple linear Cox model, an elastic net Cox model, and a random forest model. The XGBoost model had a cross-validated area under the curve value of .73 at 1 year, which was significantly superior to the other models, and it accurately predicted for countries excluded while training. It predicted close to 0% and >30% mortality more often than other models at 1 year, while maintaining good calibration. The 5-year survival was 94.7% in the 25% of patients at lowest risk and 62.3% in the 25% at highest risk. Within disease and donor subgroups, XGBoost outperformed the best univariate predictor. We visualized the effect of the main predictors-diagnosis, performance score, patient age and donor type-using the SHAP ML explainer and developed a stand-alone application, which can predict using the model and visualize predictions. The risk of mortality after HSCT for inborn errors can be accurately predicted using an explainable machine learning model. This exceeds the performance of models described in the literature. Doing so can help detect deviations from expected survival and improve risk stratification in trials.(c) 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Show less
With an increasing number of young patients surviving into adulthood after hematopoietic stem cell transplantation (HSCT), gonadal dysfunction becomes an important late effect with significant... Show moreWith an increasing number of young patients surviving into adulthood after hematopoietic stem cell transplantation (HSCT), gonadal dysfunction becomes an important late effect with significant impact on quality of life. In this retrospective study, we evaluated the exposure of busulfan (Bu) and treosulfan (Treo) in relation to gonadal function in pediatric patients who underwent HSCT for a nonmalignant disease between 1997 and 2018. In the Bu group, 56 patients could be evaluated, and gonadal dysfunction was found in 35 (63%). Lower Bu exposure (ie, cumulative area under the curve [AUC] <70 mg*h/L) was not associated with a reduced risk of gonadal dysfunction (odds ratio [OR], .92; 95% confidence interval [CI], .25 to 3.49; P = .90). In the Treo cohort, 32 patients were evaluable and gonadal insufficiency occurred in 9 patients (28%). Lower Treo exposure (AUC <1750 mg*h/L on day 1) was not associated with a reduced risk of gonadal dysfunction (OR, 1.6; 95% CI, .16 to 36.6; P = .71). Our data do not support the premise that reduced-intensity Bu-based conditioning reduces the risk for gonadal toxicity, and it is unlikely that therapeutic drug monitoring-based reduced treosulfan exposure will further limit the risk of gonadal dysfunction. (c) 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Show less
Treosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favourable efficacy and toxicity profile.... Show moreTreosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favourable efficacy and toxicity profile. Treosulfan is used in standardized dosing regimens based on body surface area. The relationship between systemic treosulfan exposure, early and long term clinical outcome in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for non-malignant diseases is unresolved. In this thesis we aimed to answer these questions. We found a relationship between the level of exposure to treosulfan and acute toxicity, but we found no relationship with the risk of rejection, survival and long-term endocrine complications. A personalized dose of treosulfan can therefore be useful to reduce toxicity in children, but because the toxicity profile of treosulfan is generally relatively mild, it will not be necessary in most cases. This is beneficial, because measuring blood levels is not always available in every hospital. Future research should focus on specific disease categories or patient groups that may benefit from treosulfan monitoring. More research is also needed on the late complications of treosulfan, such as dental, neurocognitive, hair, eye and lung problems, as this aspect becomes increasingly important as more (very young) patients undergo stem cell transplantation. Show less
Primary endpoints in pediatric clinical trials are currently very similar to those in adult trials1, and focus on quantifying or counting hard endpoints like mortality, hospital admissions and... Show morePrimary endpoints in pediatric clinical trials are currently very similar to those in adult trials1, and focus on quantifying or counting hard endpoints like mortality, hospital admissions and length of stay. Additionally, biochemical biomarkers in serum are often measured to assess drug effects on a biochemical level. The occurrence of mortality and hospital admissions is rare thanks to the improvements in clinical care that have occurred in the last century, and adopting these as primary endpoints in clinical trials gives disproportional weight to rare events which most patients will not experience. Conversely, length of stay for many clinical conditions is short, and this duration only captures a small part of the clinical recovery trajectory that patients must undergo. This dissertation described the development, technical validation and clinical validation of a new type of clinical endpoints ('value based endpoints') and a new clinical trial paradigm (The remote clinical trial), consisting of digital endpoints and non-invasive pharmacokinetic sampling. Both have the potential to transform pediatric clinical trials and pediatric clinical care. The process towards implementation is challenging and can only proceed after a rigorous validation process. The current work provides a roadmap towards selection, validation, and implementation of digital endpoints, and describes preliminary steps taken for several candidates. The digital endpoints investigated in this work fulfill several validation criteria in a range of clinical conditions and, combined with non-invasive pharmacokinetics, may move the pediatric clinical trial completely towards the home. Show less
Stoep, M.Y.E.C. van der; Bertaina, A.; Moes, D.J.A.R.; Algeri, M.; Bredius, R.G.M.; Smiers, F.J.W.; ... ; Lankester, A.C. 2022
Treosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favorable efficacy and toxicity profile.... Show moreTreosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favorable efficacy and toxicity profile. Treosulfan is used in standardized dosing regimens based on body surface area. The relationships between systemic treosulfan exposure and early and long-term clinical outcomes in pediatric patients undergoing allogeneic HSCT for nonmalignant diseases remain unclear. In this a multicenter, prospective observational study, we assessed the association between treosulfan exposure and early and, in particular, long-term clinical outcomes. Our study cohort comprised 110 pediatric patients with nonmalignant diseases who underwent HSCT between 2011 and 2019 in Leiden, The Netherlands and Rome, Italy. Blood samples were collected, and treosulfan area under the receiver operating characteristic curve (AUC0-1) was estimated as a measure of exposure. Cox proportional hazard survival analyses were performed to assess the relationships between treosulfan exposure and overall survival (OS) and event-free survival (EFS). The predictive value of systemic treosulfan exposure for the occurrence of toxicity within 28 days was evaluated using a multivariable logistic regression analysis. In the overall cohort, OS and EFS at 2 years were 89.0% and 75.3%, respectively, with an excellent OS of 97% in children age 2 years. The occurrence of grade II-IV acute graft-versus-host disease, the level of 1-year whole blood chimerism, and 2-year OS and EFS were not correlated with treosulfan exposure. The occurrence of skin toxicity (odds ratio [OR], 3.97; 95% confidence interval [CI], 1.2613.68; P = .02) and all-grade mucositis (OR, 4.43; 95% CI, 1.43-15.50; P = .02), but not grade 2 mucositis (OR, 1.51; 95% CI, 0.52 to 4.58; P = .46) was related to high treosulfan exposure (>1750 mg*h/L). Our study demonstrates that standardized treosulfan-based conditioning results in a favorable OS and EFS in infants and children with nonmalignant diseases, independent of interindividual variation in treosulfan exposure. These outcomes can be achieved without the need for therapeutic drug monitoring, thereby emphasizing the advantage of treosulfan use in this category of patients. Although higher treosulfan exposure increases the risk of skin toxicity, there is no absolute necessity for therapeutic drug monitoring if proper preventive skin measures are taken. More research is needed to assess whether deescalation of treosulfan doses is possible to minimize early and long-term toxicity without compromising efficacy. (c) 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Show less
Amaruddin, A.I.; Koopman, J.P.R.; Muhammad, M.; Versteeg, S.A.; Wahyuni, S.; Ree, R. van; ... ; Sartono, E. 2021
Background: There is not much known about venom allergy in tropical regions. Here, we studied the prevalence of specific IgE (sIgE) and skin prick test (SPT) reactivity and reported sting-related... Show moreBackground: There is not much known about venom allergy in tropical regions. Here, we studied the prevalence of specific IgE (sIgE) and skin prick test (SPT) reactivity and reported sting-related symptoms, in high- and low-socioeconomic status (SES) schoolchildren living in urban city of Makassar in Indonesia. Methods: Children from high- (n = 160) and low- (n = 165) SES schools were recruited. Standardized questionnaires were used to record information on allergic disorders as well as sting-related symptoms. Parasitic infection, SPT reactivity, and sIgE to Apis mellifera (bee-venom) as well as Vespula spp. (wasp-venom) were assessed. Results: SPT reactivity to bee- and wasp-venom was 14.3 and 12.7%, while the prevalence of sIgE was 26.5 and 28.5%, respectively. When SES was considered, prevalence of SPT to bee- and wasp-venom was higher in high-SES than in low-SES schoolchildren (bee: 22.8 vs. 5.7%, p < 0.001; and wasp: 19.6 vs. 5.7%, p < 0.001). Conversely, sIgE to both venoms was lower in high-SES than in low-SES (bee: 19 vs. 34%, p = 0.016; and wasp: 19 vs. 38%, p = 0.003). Furthermore, among SPT positive subjects, considerable proportion had no detectable sIgE to bee- (65.85%) or wasp-venom (66.67%). Altogether the sensitizations were rarely translated into clinical reaction, as only 1 child reported significant local reaction after being stung. No association with parasitic infections was found. Show less
Dondorp, W.; Bolt, I.; Tibben, A.; Wert, G. de; Summeren, M. van 2021
In debates about genetic testing of children, as well as about disclosing unsolicited findings (UFs) of pediatric exome sequencing, respect for future autonomy should be regarded as a prima facie... Show moreIn debates about genetic testing of children, as well as about disclosing unsolicited findings (UFs) of pediatric exome sequencing, respect for future autonomy should be regarded as a prima facie consideration for not taking steps that would entail denying the future adult the opportunity to decide for herself about what to know about her own genome. While the argument can be overridden when other, morally more weighty considerations are at stake, whether this is the case can only be determined in concrete cases. Importantly, when children grow into adolescents, respect for future autonomy will have to give way to respecting their emerging autonomy. When pediatric exome sequencing is done for complex conditions not involving developmental delay, respect for the child's future or emerging autonomy should be a primary consideration for those charged with deciding on behalf of the child. Building on what Emanuel and Emanuel have termed the 'deliberative model' of shared decision making, we argue that if parents fail to give these considerations their due, professionals should actively invite them to do so. Taking a directive stance may be needed in order to make sure that the future or emerging autonomy of the child are duly considered in the decision-making process, but also to help the parents and themselves to shape their respective roles as responsible care-givers. Show less
Ethnic differences in cardiovascular risk factors and disease are well-known and may originate in early-life. We examined the ethnic differences in cardiac structure and function in children using... Show moreEthnic differences in cardiovascular risk factors and disease are well-known and may originate in early-life. We examined the ethnic differences in cardiac structure and function in children using cardiac magnetic resonance imaging in a European migrant population, and whether any difference was explained by early life factors. We used a prospective population-based cohort study among 2317 children in Rotterdam, the Netherlands. We compared children from Dutch (73%), Cape Verdean (3.5%), Dutch Antillean (3.3%), Moroccan (6.1%), Surinamese-Creoles (3.9%), Surinamese-Hindustani (3.4%), and Turkish (6.4%) background. Main outcomes were cMRI-measured cardiac structures and function. Cardiac outcomes were standardized on body surface area. Cape Verdean, Surinamese-Hindustani, and Turkish children had smaller right ventricular end-diastolic volume and left ventricular end-diastolic volume relative to their body size than Dutch children (p < 0.05). These results were not fully explained by fetal and childhood factors. Right ventricular ejection fraction and left ventricular ejection fraction did not differ between ethnicities after adjustment for fetal and childhood factors. Conclusion: Right ventricular end-diastolic volume and left ventricular end-diastolic volume differ between ethnic subgroups in childhood, without affecting ejection fraction. Follow-up studies are needed to investigate whether these differences lead to ethnic differences in cardiac disease in adulthood.What is Known:center dot Ethnic differences in cardiovascular risk factors and disease are well-known and may originate in early-life.center dot The prevalence of cardiovascular disease differs between ethnic groups. What is New:center dot We examined ethnic differences in left and right cardiac structure and function in children using cMRI.center dot Right and left cardiac dimensions differ between ethnic groups in childhood and are only partly explained by fetal and childhood factors. Show less
Ven, J.P.G. van der; Alsaied, T.; Juggan, S.; Bossers, S.S.M.; Bosch, E. van den; Kapusta, L.; ... ; Helbing, W.A. 2020
Objective: To assess the role of atrial function on exercise capacity and clinical events in Fontan patients.Design: We included 96 Fontan patients from6 tertiary centers, aged 12.8 (IQR 10.1-15.6)... Show moreObjective: To assess the role of atrial function on exercise capacity and clinical events in Fontan patients.Design: We included 96 Fontan patients from6 tertiary centers, aged 12.8 (IQR 10.1-15.6) years, who underwent cardiacmagnetic resonance imaging and cardiopulmonary exercise testing within 12 months of each other from 2004 to 2017. Intra-atrial lateral tunnel (ILT) and extracardiac conduit (ECC) patients were matched 1:1 with regard to age, gender and dominant ventricle. The pulmonary venous atrium was manually segmented in all phases and slices. Atrial function was assessed by volume-time curves. Furthermore, atrial longitudinal and circumferential feature tracking strain was assessed. We determined the relation between atrial function and exercise capacity, assessed by peak oxygen uptake and VE/VCO2 slope, and events (mortality, listing for transplant, re-intervention, arrhythmia) during follow-up.Results: Atrial maximal and minimal volumes did not differ between ILT and ECC patients. ECC patients had higher reservoir function (21.1 [16.4-28.0]% vs 18.2 [10.9-22.2]%, p =.03), lower conduit function and lower total circumferential strain (13.8 +/- 5.1% vs 18.0 +/- 8.7%, p =.01), compared to ILT patients. Only for ECC patients, a better late peak circumferential strain rate predicted better VE/VCO2 slope. No other parameter of atrial function predicted peak oxygen uptake or VE/VCO2 slope. During a median follow-up of 6.2 years, 42 patients reached the composite end-point. No atrial function parameters predicted events during follow-up.Conclusions: ECC patients have higher atrial reservoir function and lower conduit function. Atrial function did not predict exercise capacity or events during follow-up. (c) 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Show less
Background The following position statement from the Union of the European Phoniatricians, updated on 25th May 2020 (superseding the previous statement issued on 21st April 2020), contains a series... Show moreBackground The following position statement from the Union of the European Phoniatricians, updated on 25th May 2020 (superseding the previous statement issued on 21st April 2020), contains a series of recommendations for phoniatricians and ENT surgeons who provide and/or run voice, swallowing, speech and language, or paediatric audiology services. Objectives This material specifically aims to inform clinical practices in countries where clinics and operating theatres are reopening for elective work. It endeavours to present a current European view in relation to common procedures, many of which fall under the aegis of aerosol generating procedures. Conclusion As evidence continues to build, some of the recommended practices will undoubtedly evolve, but it is hoped that the updated position statement will offer clinicians precepts on safe clinical practice. Show less
Recently a framework was presented to assess whether pediatric covariate models for clearance can be extrapolated between drugs sharing elimination pathways, based on extraction ratio, protein... Show moreRecently a framework was presented to assess whether pediatric covariate models for clearance can be extrapolated between drugs sharing elimination pathways, based on extraction ratio, protein binding, and other drug properties. Here we evaluate when a pediatric covariate function for midazolam clearance can be used to scale clearance of other CYP3A substrates. A population PK model including a covariate function for clearance was developed for midazolam in children aged 1–17 years. Commonly used CYP3A substrates were selected and using the framework, it was assessed whether the midazolam covariate function accurately scales their clearance. For eight substrates, reported pediatric clearance values were compared numerically and graphically with clearance values scaled using the midazolam covariate function. For sildenafil, clearance values obtained with population PK modeling based on pediatric concentration-time data were compared with those scaled with the midazolam covariate function. According to the framework, a midazolam covariate function will lead to systemically accurate clearance scaling (absolute prediction error (PE) < 30%) for CYP3A substrates binding to albumin with an extraction ratio between 0.35 and 0.65 when binding < 10% in adults, between 0.05 and 0.55 when binding > 90%, and with an extraction ratio ranging between these values when binding between 10 and 90%. Scaled clearance values for eight commonly used CYP3A substrates were reasonably accurate (PE < 50%). Scaling of sildenafil clearance was accurate (PE < 30%). We defined for which CYP3A substrates a pediatric covariate function for midazolam clearance can accurately scale plasma clearance in children. This scaling approach may be useful for CYP3A substrates with scarce or no available pediatric PK information. Show less
Growth and development affect the metabolism of drugs administered to neonates, infants, and children. Research in this thesis focused on the metabolism by cytochrome P450 (CYP) 3A enzymes, aiming... Show moreGrowth and development affect the metabolism of drugs administered to neonates, infants, and children. Research in this thesis focused on the metabolism by cytochrome P450 (CYP) 3A enzymes, aiming to predict CYP3A-mediated clearance in neonates, infants, and children, by development of pediatric (physiological) population pharmacokinetic models.CYP3A-mediated systemic metabolism of midazolam in critically ill pediatric patients was found to be impacted by body weight, critical illness, and inflammation. The developed model was subsequently found to accurately predict clearance in postoperative children or critically ill patients. Furthermore, advanced physiological modelling methods were applied to distinguish between first-pass and systemic CYP3A-mediated metabolism to elucidate the role of intestinal and hepatic CYP3A in neonates and children covering the whole pediatric age range. Lastly, it was described when a pediatric covariate function for CYP3A-mediated midazolam clearance could be applied to scale plasma clearance of other CYP3A substrates in the pediatric population.This work will significantly improve CYP3A-mediated clearance predictions in neonates, infants, and children, which will ultimately lead to rational support for pediatric doses of CYP3A substrates in first-in-child studies during drug development and for pediatric dose recommendations for CYP3A substrates in clinical practice. Show less
In this thesis, new insights in the complex and intertwined relationship between viral infections, T cells and natural killer cells after allogeneic HSCT in children are provided and discussed.... Show moreIn this thesis, new insights in the complex and intertwined relationship between viral infections, T cells and natural killer cells after allogeneic HSCT in children are provided and discussed. Patients are at high risk of viral complication during the T cell deficient period early after HSCT. When viral infections occur, interventions to bridge the period until the recovery of antiviral T cell immunity are of great importance to improve the clinical outcome after HSCT. Besides antiviral medication and the use of adoptive immunotherapy, NK cells may play a role in the protection against viruses when T cells are not available to perform their task. Show less
Neonatal brachial plexus palsy (NBPP) is a nerve injury to the brachial plexus which controls arm-movements. This thesis describes the impact of this injury on the lives of patients in terms... Show moreNeonatal brachial plexus palsy (NBPP) is a nerve injury to the brachial plexus which controls arm-movements. This thesis describes the impact of this injury on the lives of patients in terms of quality of life, participation, healthcare use and treatment outcomes. Findings in this thesis have led to important insights into the care for patients with NBPP and their families. It turns out that there is considerable information need in these patients, that NBPP has impact on families of very young patients and adult patients perceive influence of NBPP on their study and career choices. This thesis also showed that when describing outcomes of shoulder surgery (tendon-transfers) it is important to take into account treatment history because outcomes differ for children with a surgical treatment history. This may help to manage patients’ outcome expectations. A recommendation in this thesis is to develop and investigate a standardized paramedic treatment protocol for the different life-phases of NBPP patients because this is not available yet. Hereby, a more strict follow-up is very important. Furthermore, better information should be developed in order to provide NBPP patients with the information they need throughout their lifespan. Findings in this thesis can be used for this. Show less
Without a proper treatment, critical congenital heart defects (CCHD) lead to death in the first month of life. Timely diagnosis is pivotal for reducing morbidity and mortality. Pulse oximetry is... Show moreWithout a proper treatment, critical congenital heart defects (CCHD) lead to death in the first month of life. Timely diagnosis is pivotal for reducing morbidity and mortality. Pulse oximetry is used in many countries to screen newborns for CCHD. However, this screening has not been implemented in the Netherlands, because of the unique perinatal care system, with a high home birth rate and early discharge after hospital deliveries. This thesis describes research performed to assess the feasibility, accuracy, acceptability and costs of neonatal screening for CCHD with pulse oximetry in the Dutch perinatal care system. To do this, the protocol that is used in the United States and Scandinavia was adapted to fit the working scheme of community midwives. Show less
