Background The size of the margin strongly influences the required sample size in non-inferiority and equivalence trials. What is sometimes ignored, however, is that for trials with binary outcomes... Show moreBackground The size of the margin strongly influences the required sample size in non-inferiority and equivalence trials. What is sometimes ignored, however, is that for trials with binary outcomes, the scale of the margin - risk difference, risk ratio or odds ratio - also has a large impact on power and thus on sample size requirement. When considering several scales at the design stage of a trial, these sample size consequences should be taken into account. Sometimes, changing the scale may be needed at a later stage of a trial, for example, when the event proportion in the control arm turns out different from expected. Also after completion of a trial, a switch to another scale is sometimes made, for example, when using a regression model in a secondary analysis or when combining study results in a meta-analysis that requires unifying scales. The exact consequences of such switches are currently unknown. Methods and Results This article first outlines sample size consequences for different choices of analysis scale at the design stage of a trial. We add a new result on sample size requirement comparing the risk difference scale with the risk ratio scale. Then, we study two different approaches to changing the analysis scale after the trial has commenced: (1) mapping the original non-inferiority margin using the event proportion in the control arm that was anticipated at the design stage or (2) mapping the original non-inferiority margin using the observed event proportion in the control arm. We use simulations to illustrate consequences on type I and type II error rates. Methods are illustrated on the INES trial, a non-inferiority trial that compared single birth rates in subfertile couples after different fertility treatments. Our results demonstrate large differences in required sample size when choosing between risk difference, risk ratio and odds ratio scales at the design stage of non-inferiority trials. In some cases, the sample size requirement is twice as large on one scale compared with another. Changing the scale after commencing the trial using anticipated proportions mainly impacts type II error rate, whereas switching using observed proportions is not advised due to not maintaining type I error rate. Differences were more pronounced with larger margins. Conclusions Trialists should be aware that the analysis scale can have large impact on type I and type II error rates in non-inferiority trials. Show less
Introduction Neurodevelopmental delay is more common in children born with congenital heart defects (CHD), even with optimal perinatal and peri-operative care. It is hypothesized that fetuses with... Show moreIntroduction Neurodevelopmental delay is more common in children born with congenital heart defects (CHD), even with optimal perinatal and peri-operative care. It is hypothesized that fetuses with CHD are prone to neurological impairment in utero due to their cardiac defect, possibly leading to delayed cortical development. Methods Cerebral cortical maturation was assessed with advanced neurosonographic examinations every 4 weeks in fetuses with CHD and compared to control fetuses. Five different primary fissures and four areas were scored (ranging 0-5) by blinded examiners using a cortical maturation scheme. Results Cortical staging was assessed in 574 ultrasound examinations in 85 CHD fetuses and 61 controls. Small differences in grading were seen in Sylvian and cingulate fissures. (Sylvian fissure: -0.12 grade, 95% CI (-0.23; -0.01) p = 0.05, cingulate fissure: -0.24 grade, 95% CI (-0.38; -0.10) p = <0.001. Other cortical areas showed normal maturation as compared to control fetuses. Conclusion Small differences were seen in three of the nine analyzed cortical areas in CHD fetuses, in contrast to previous reports on progressive third-trimester delay. The clinical implications of the small differences however, remain unknown. Show less
Objectives Functional development of the fetal cardiac autonomic nervous system (cANS) plays a key role in fetal maturation and can be assessed through fetal heart rate variability (fHRV)-analysis,... Show moreObjectives Functional development of the fetal cardiac autonomic nervous system (cANS) plays a key role in fetal maturation and can be assessed through fetal heart rate variability (fHRV)-analysis, with each HRV parameter representing different aspects of cANS activity. Current available techniques, however, are unable to assess the fHRV parameters accurately throughout the whole pregnancy. This study aims to test the feasibility of color tissue Doppler imaging (cTDI) as a new ultrasound technique for HRV analysis. Secondly, we explored time trends of fHRV parameters using this technique.Methods 18 healthy singleton fetuses were examined sequentially every 8 weeks from 10 weeks GA onwards. From each examination, 3 cTDI recordings of the four-chamber view of 10 seconds were retrieved to determine accurate beat-to-beat intervals. The fHRV parameters SDNN, RMSSD, SDNN/RMSSD, and pNN10, each representing different functional aspects of the cANS, were measured, and time trends during pregnancy were explored using spline functions within a linear mixed-effects model.Results In total, 77% (95% Cl 66-87%) of examinations were feasible for fHRV analysis from the first trimester onwards, which is a great improvement compared to other techniques. The technique is able to determine different maturation rates of the fHRV parameters, showing that cANS function, presumably parasympathetic activity, establishes around 20 weeks GA and matures rapidly until 30 weeks GA.Conclusions This is the first study able to assess cANS function through fHRV analysis from the first trimester onwards. The use of cTDI to determine beat-to-beat intervals seems feasible in just 3 clips of 10 seconds, which holds promise for future clinical use in assessing fetal well-being. Show less
Boer, F.L.; Eikelder, M.L.G. ten; Geloven, N. van; Kapiteijn, E.H.; Gaarenstroom, K.N.; Hughes, G.; ... ; Poelgeest, M.I.E. van 2021
Objective. To identify clinicopathological characteristics, treatment patterns, clinical outcomes and prognostic factors in patients with vulvar melanoma (VM). Materials & methods. This... Show moreObjective. To identify clinicopathological characteristics, treatment patterns, clinical outcomes and prognostic factors in patients with vulvar melanoma (VM). Materials & methods. This retrospective multicentre cohort study included 198 women with VM treated in eight cancer centres in the Netherlands and UK between 1990 and 2017. Clinicopathological features, treatment, recurrence, and survival data were collected. Overall and recurrence-free survival was estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariable Cox regression analysis. Results. The majority of patients (75.8%) had localized disease at diagnosis. VM was significantly associated with high-riskclinicopathological features, including age, tumour thickness, ulceration, positive resection margins and involved lymph nodes. Overall survival was 48% (95% CI 40?56%) and 31% (95% CI 23?39%) after 2 and 5 years respectively and did not improve in patients diagnosed after 2010 compared to patients diagnosed between 1990 and 2009. Recurrence occurred in 66.7% of patients, of which two-third was non-local. In multivariable analysis, age and tumour size were independent prognostic factors for worse survival. Prognostic factors for recurrence were tumour size and tumour type. Only the minority of patients were treated with immuno- or targeted therapy. Conclusion. Our results show that even clinically early-stage VM is an aggressive disease associated with poor clinical outcome due to distant metastases. Further investigation into the genomic landscape and the immune microenvironment in VM may pave the way to novel therapies to improve clinical outcomes in these aggressive tumours. Clinical trials with immunotherapy or targeted therapy in patients with high-risk, advanced or metastatic disease are highly needed.Objective. To identify clinicopathological characteristics, treatment patterns, clinical outcomes and prognostic factors in patients with vulvar melanoma (VM).Materials & methods. This retrospective multicentre cohort study included 198 women with VM treated in eight cancer centres in the Netherlands and UK between 1990 and 2017. Clinicopathological features, treatment, recurrence, and survival data were collected. Overall and recurrence-free survival was estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariable Cox regression analysis.Results. The majority of patients (75.8%) had localized disease at diagnosis. VM was significantly associated with high-riskclinicopathological features, including age, tumour thickness, ulceration, positive resection margins and involved lymph nodes. Overall survival was 48% (95% CI 40-56%) and 31% (95% CI 23-39%) after 2 and 5 years respectively and did not improve in patients diagnosed after 2010 compared to patients diagnosed between 1990 and 2009. Recurrence occurred in 66.7% of patients, of which two-third was non-local. In multivariable analysis, age and tumour size were independent prognostic factors for worse survival. Prognostic factors for recurrence were tumour size and tumour type. Only the minority of patients were treated with immuno-or targeted therapy.Conclusion. Our results show that even clinically early-stage VM is an aggressive disease associated with poor clinical outcome due to distant metastases. Further investigation into the genomic landscape and the immune microenvironment in VM may pave the way to novel therapies to improve clinical outcomes in these aggressive tumours. Clinical trials with immunotherapy or targeted therapy in patients with high-risk, advanced or metastatic disease are highly needed. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Show less
Metzemaekers, J.; Lust, E.E.R.; Rhemrev, J.P.T.; Geloven, N. van; Twijnstra, A.R.H.; Westerlaken, L. van der; Jansen, F.W. 2021
Background: Subfertility occurs in 30-40% of endometriosis patients. Regarding the fertilisation rate with in vitro fertilisation (IVF) and endometriosis, conflicting data has been published. This... Show moreBackground: Subfertility occurs in 30-40% of endometriosis patients. Regarding the fertilisation rate with in vitro fertilisation (IVF) and endometriosis, conflicting data has been published. This study aimed to compare endometriosis patients to non-endometriosis cycles assessing fertilisation rates in IVF.Methods: A population-based cohort study was conducted at the Leiden University Medical Center. IVF cycles of endometriosis patients and controls (unexplained infertility and tubal pathology) were analysed. The main outcome measurement was fertilisation rate.Results: 503 IVF cycles in total, 191 in the endometriosis group and 312 in the control. The mean fertilisation rate after IVF did not differ between both groups, 64.1%+/- 25.5 versus 63.9%+/- 24.8 (p=0.95) respectively, independent of age and r-ASRM classification. The median number of retrieved oocytes was lower in the endometriosis group (7.0 versus 8.0 respectively, p=0.19) and showed a significant difference when corrected for age (p=0.02). When divided into age groups, the statistical effect was only seen in the group of <= 35 years (p=0.04). In the age group <= 35, the endometriosis group also showed significantly more surgery on the internal reproductive organs compared to the control group (p<0.001). All other outcomes did not show significant differences.Conclusion: Similar fertilisation rates were found in endometriosis IVF cycles compared to controls. The oocyte retrieval was lower in the endometriosis group, however this effect was only significant in the age group <= 35 years. All other secondary outcomes did not show significant differences. In general, endometriosis patients with an IVF indication can be counselled positively regarding the chances of becoming pregnant, and do not need a different IVF approach. Show less
The incident/dynamic time-dependent AUC (Area Under the ROC Curve) is an appealing measure to express the discriminative value of a dynamic survival model over time. However, estimation of this... Show moreThe incident/dynamic time-dependent AUC (Area Under the ROC Curve) is an appealing measure to express the discriminative value of a dynamic survival model over time. However, estimation of this measure is not straightforward. Four recently proposed estimation approaches are studied. In an extensive simulation study, a head-to-head comparison between these four estimation methods is made. The estimation algorithms of some of the methods are extended. Results are illustrated with a motivating dynamic survival model from Reproductive Medicine. (C) 2020 The Authors. Published by Elsevier B.V. Show less
Meijer, C.R.; Akker, M.E. van den; Bodegom, L. van; Escher, J.C.; Geloven, N. van; Overveld, F. van; ... ; Mearin, M.L. 2021
Introduction Coeliac disease (CD) occurs in 1% of the population, develops early in life and is severely underdiagnosed. Undiagnosed and untreated disease is associated with short-term and long... Show moreIntroduction Coeliac disease (CD) occurs in 1% of the population, develops early in life and is severely underdiagnosed. Undiagnosed and untreated disease is associated with short-term and long-term complications. The current healthcare approach is unable to solve the underdiagnosis of CD and timely diagnosis and treatment is only achieved by active case finding. Aim: to perform a case finding project to detect CD children who visit the Youth Health Care Centres (YHCCs) in a well-described region in the Netherlands to evaluate whether it is feasible, cost-effective and well accepted by the population.Methods/analysis Prospective intervention cohort study. Parents of all children aged 12 months and 4 years attending the YHCCs for a regular visit are asked whether their child has one or more CD-related symptoms from a standardised list. If so, they will be invited to participate in the case finding study. After informed consent, a point of care test (POCT) to assess CD-specific antibodies against tissue transglutaminase (TG2A) is performed onsite the YHCCs. If the POCT is positive, CD is highly suspected and the child will be referred to hospital for definitive diagnosis according to the Guideline Coeliac Disease of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition guideline.Main outcomes1. Incidence rate of new CD diagnoses in the study region in comparison to the one in the same age diagnosed by standard of care in the rest of the Netherlands.2. Feasibility and cost-effectiveness of active CD case finding at the YHCCs. All costs of active case finding, diagnostics and treatment of CD and the potential short-term and long-term consequences of the disease will be calculated for the setting with and without case finding.1. Ethical acceptability: by questionnaires on parental and healthcare professionals' satisfaction.A statistical analysis plan was prepared and is published on the GLUTENSCREEN website () and added as annex 1).Ethics and disseminationThe Medical Ethics Committee Leiden approved this study. If we prove that case finding at the YHCC is feasible, cost-effective and well accepted by the population, implementation is recommended. Show less
Introduction Respiratory tract infections (RTIs) affect children all over the world and are associated with significant morbidity and mortality. In particular, recurrent RTIs cause a high burden of... Show moreIntroduction Respiratory tract infections (RTIs) affect children all over the world and are associated with significant morbidity and mortality. In particular, recurrent RTIs cause a high burden of disease and lead to frequent doctor visits. Children with recurrent RTIs generally have no significant alterations or deficits in systemic immunity. In an attempt to treat the assumed bacterial component involved, they are often treated with prolonged courses of prophylactic antibiotics taken on a daily basis. Despite its common use, there is no evidence that this is beneficial. Studies assessing the clinical effectiveness of antibiotic prophylaxis as well as potential adverse effects and antibiotic resistance development, are therefore urgently needed. Methods and analysis We present a protocol for a randomised double-blind placebo-controlled trial comparing co-trimoxazole with placebo treatment in children with recurrent RTIs. A total of 158 children (aged 6 months-10 years) with recurrent RTIs without significant comorbidity will be enrolled from a minimum of 10 Dutch hospitals. One group receives co-trimoxazole 18 mg/kg two times per day (36 mg/kg/day) and the other group receives a placebo two times per day for a period of 3 months. The main objective is to determine whether antibiotic prophylaxis is more effective than placebo to prevent/reduce respiratory symptoms in children with recurrent RTIs. Respiratory symptoms will be scored by parents on a daily basis in both study arms by the use of a mobile phone application. Our primary outcome will be the number of days with at least two respiratory symptoms during the treatment. Ethics and dissemination Ethics approval was obtained from the Medical Ethics Research Committee Zuidwest Holland/LDD. A manuscript with the study results will be submitted to a peer-reviewed journal. All participants will be informed about the study results. The results of the study will inform clinical guidelines regarding the prophylactic treatment of children with recurrent RTIs. Show less
Wind, M.; Hendriks, M.; Brussel, B.T.J. van; Eikenboom, J.; Allaart, C.F.; Lamb, H.J.; ... ; Teng, Y.K.O. 2021
Objectives SLE and/or antiphospholipid syndrome (SLE/APS) are complex and rare systemic autoimmune diseases that predominantly affect women of childbearing age. Women with SLE/APS are at high risk... Show moreObjectives SLE and/or antiphospholipid syndrome (SLE/APS) are complex and rare systemic autoimmune diseases that predominantly affect women of childbearing age. Women with SLE/APS are at high risk of developing complications during pregnancy. Therefore, clinical practice guidelines recommend that patients with SLE/APS should receive multidisciplinary counselling before getting pregnant. We investigated the clinical effectiveness of implementing a multidisciplinary clinical pathway including prepregnancy counselling of patients with SLE/APS. Methods A clinical pathway with specific evaluation and prepregnancy counselling for patients with SLE/APS was developed and implemented in a tertiary, academic hospital setting. Patients were prospectively managed within the clinical pathway from 2014 onwards and compared with a retrospective cohort of patients that was not managed in a clinical pathway. Primary outcome was a combined outcome of disease flares for SLE and thromboembolic events for APS. Secondary outcomes were maternal and fetal pregnancy complications. Results Seventy-eight patients with 112 pregnancies were included in this study. The primary combined outcome was significantly lower in the pathway cohort (adjusted OR (aOR) 0.20 (95% CI 0.06 to 0.75)) which was predominantly determined by a fivefold risk reduction of SLE flares (aOR 0.22 (95% CI 0.04 to 1.09)). Maternal and fetal pregnancy complications were not different between the cohorts (respectively, aOR 0.91 (95% CI 0.38 to 2.17) and aOR 1.26 (95% CI 0.55 to 2.88)). Conclusions The outcomes of this study suggest that patients with SLE/APS with a pregnancy wish benefit from a multidisciplinary clinical pathway including prepregnancy counselling. Show less
Welie, N. van; Rosielle, K.; Dreyer, K.; Rijswijk, J. van; Lambalk, C.B.; Geloven, N. van; ... ; H2Oil Study Grp 2020
Research question: Does the fertility-enhancing effect of tubal flushing during hysterosalpingography (HSG) with oil-based contrast change over time?Design: This was a secondary analysis of the... Show moreResearch question: Does the fertility-enhancing effect of tubal flushing during hysterosalpingography (HSG) with oil-based contrast change over time?Design: This was a secondary analysis of the H2Oil (long-term follow-up) study, a multicentre randomized controlled trial evaluating the effectiveness of oil-based and water-based contrast during HSG. The main outcome was ongoing pregnancy. Cox proportional hazards models for time to ongoing pregnancy were fitted over 3 years of follow-up.Results: Data on 1107 couples were available; 550 couples had oil-based contrast and 557 water-based contrast at HSG. Ongoing pregnancy rates after 3 years were 77% and 71%, respectively. Median follow-up was 9-10 months (5th-95th percentile: <1 to 36). The hazard ratio for ongoing pregnancy for oil versus water over 3 years of follow-up was 1.26 (95% confidence interval [CI] 1.10-1.45). The scaled Schoenfeld residual plots showed a decrease in hazard ratio that was linear with log-transformed time. After including an interaction with log-transformed time, the hazard ratio immediately after HSG was 1.71 (95% CI 1.27-2.31) and reduced to no effect (hazard ratio of 1) at approximately 2 years. There was no evidence for a change in hazard ratio over time in a subgroup of women who experienced pain during HSG.Conclusions: The hazard ratio for ongoing pregnancy of oil-based versus water-based contrast was 1.71 immediately after HSG, gradually decreasing and plateauing towards a hazard ratio of 1 (indicating no effect) after approximately 2 years. This supports the hypothesis that oil-based contrast might dislodge debris or mucus plugs from the Fallopian tubes, but this has yet to be definitively proved. Show less
Palen, R.L.F. van der; Baart, S.J.; Geloven, N. van; Hazekamp, M.G.; Blom, N.A. 2020
Objectives Presumably, changes in fetal circulation contribute to the delay in maturation of the cortex in fetuses with congenital heart defect (CHD). The aim of the current study is to analyze... Show moreObjectives Presumably, changes in fetal circulation contribute to the delay in maturation of the cortex in fetuses with congenital heart defect (CHD). The aim of the current study is to analyze fetal brain development based on hemodynamic differences, using novel brain-age prediction software. Methods We have performed detailed neurosonography, including acquiring 3D volumes, prospectively in cases with isolated CHD from 20 weeks onwards. An algorithm that assesses the degree of fetal brain-age automatically was used to compare CHD cases to controls. We stratified CHD cases according to flow and oxygenation profiles by lesion physiology and performed subgroup analyses. Results A total of 616 ultrasound volumes of 162 CHD cases and 75 controls were analyzed. Significant differences in maturation of the cortex were observed in cases with normal blood flow toward the brain (-3.8 days, 95%CI [-5.5; -2.0],P = <.001) and low (-4.0 days, 95% CI [-6.7; -1.2]P = <.05; hypoplastic left heart syndrome[HLHS]) and mixed (-4.4 days, 95%CI [-6.4; -2.5]p = <.001) oxygen saturation in the ascending aorta (TGA) and in cardiac mixing (eg, Fallot) cases. Conclusion The current study shows significant delay in brain-age in TGA and Fallot cases as compared to control cases. However, the small differences found in this study questions the clinical relevance. Show less
Geloven, N. van; Swanson, S.A.; Ramspek, C.L.; Luijken, K.; Diepen, M. van; Morris, T.P.; ... ; Cessie, S. le 2020
In this paper we study approaches for dealing with treatment when developing a clinical prediction model. Analogous to the estimand framework recently proposed by the European Medicines Agency for... Show moreIn this paper we study approaches for dealing with treatment when developing a clinical prediction model. Analogous to the estimand framework recently proposed by the European Medicines Agency for clinical trials, we propose a 'predictimand' framework of different questions that may be of interest when predicting risk in relation to treatment started after baseline. We provide a formal definition of the estimands matching these questions, give examples of settings in which each is useful and discuss appropriate estimators including their assumptions. We illustrate the impact of the predictimand choice in a dataset of patients with end-stage kidney disease. We argue that clearly defining the estimand is equally important in prediction research as in causal inference. Show less
Aim: To test whether stabilising very preterm infants while performing physiological-based cord clamping (PBCC) is at least as effective as the standard approach of time-based delayed cord clamping... Show moreAim: To test whether stabilising very preterm infants while performing physiological-based cord clamping (PBCC) is at least as effective as the standard approach of time-based delayed cord clamping (DCC).Methods: A randomised controlled non-inferiority study was performed in two centres from May until November 2018, including preterm infants born below 32 weeks of gestational age. Infants were allocated to PBCC or standard DCC. Infants receiving PBCC were stabilised on a purpose-built resuscitation table with an intact umbilical cord. The cord was clamped when the infant had regular spontaneous breathing, heart rate >= 100 bpm and SpO(2) 90% while using FiO(2) 0.40. In infants receiving DCC, the cord was clamped at 30 60 seconds after birth before they were transferred to the standard resuscitation table for further treatment and stabilisation. Primary outcome was time to reach respiratory stability.Results: Thirty-seven infants (mean gestational age 29+0 weeks) were included. Mean cord clamping time was 5:49 +/- 2:37 min in the PBCC (n = 20) and 1:02 +/- 0:30 min in the DCC group (n = 17). Infants receiving PBCC needed less time to reach respiratory stability (PBCC 5:54 +/- 2:27 min; DCC 7:07 +/- 2:54 min; mean difference corrected for gestational age 1:19 min, 95 degrees 6 CI [3:04 0:27]), showing non-inferiority with the pre-defined limit of 1:15 min. No significant differences between the groups were found for maternal blood loss, postpartum haemorrhage, infant temperature at admission or short-term neonatal outcomes.Conclusion: Stabilisation of very preterm infants with physiological-based cord clamping is at least as effective as with standard DCC. Show less
Objective Neurodevelopmental delay is frequently encountered in children with a congenital heart defect (CHD). Fetuses with major CHD have a smaller head circumference (HC), irrespective of altered... Show moreObjective Neurodevelopmental delay is frequently encountered in children with a congenital heart defect (CHD). Fetuses with major CHD have a smaller head circumference (HC), irrespective of altered cerebral flow or brain oxygenation. This cohort study compared head growth in cases with isolated vs those with non-isolated CHD to evaluate the effect of additional pathology on head size in these fetuses.Method All CHD cases diagnosed prenatally in the period January 2002-July 2014 were selected from our regional registry, PRECOR. Cases of multiple pregnancy, and those affected by maternal diabetes, severe fetal structural brain anomalies or functional CHD were excluded. Subjects were divided into groups according to whether the CHD was isolated, and the non-isolated group was subdivided into three groups: cases with genetic anomaly, extracardiac malformation or placental pathology. In both isolated and non-isolated CHD groups, CHDs were also grouped according to their potential effect on aortic flow and oxygen saturation. Mean HC Z-scores at 20 weeks and increase or decrease (Delta) ofHCZ-scores over the course of pregnancy were compared between isolated and non-isolated groups, using mixed linear regression models.Results Included were 916 cases of CHD diagnosed prenatally, of which 378 (41.3%) were non-isolated (37 with placental pathology, 217 with genetic anomaly and 124 with extracardiac malformation). At 20 weeks, non-isolated cases had significantly lower HC Z-scores than did isolated cases ( Z-score = -0.70 vs -0.03; P < 0.001) and head growth over the course of pregnancy showed a larger decrease in this group (Delta HC Z-score = -0.03 vs -0.01 per week; P = 0.01). Cases with placental pathology had the lowest HC Z-score at 20 weeks ( Z-score = -1.29) and the largest decrease in head growth (Delta HC Z-score= -0.06 per week). In CHD subjects with a genetic diagnosis (Z-score = -0.73; Delta HC Z-score = -0.04 per week) and in those with an extracardiac malformation (Z-score = -0.49; Delta HC Z-score = -0.02 per week), HC Z-scores were also lower compared with those in subjects with isolated CHD. CHDs that result in low oxygenation or flow to the brain were present more frequently in isolated than in non-isolated cases.Conclusions Smaller HC in fetuses with CHD appears to be associated strongly with additional pathology. Placental pathology and genetic anomaly in particular seem to be important contributors to restricted head growth. This effect appears to be irrespective of altered hemodynamics caused by the CHD. Previously reported smaller HC in CHD should, in our opinion, be attributed to additional pathology. Neurodevelopment studies in infants with CHD should, therefore, always differentiate between isolated and non-isolated cases. (c) 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. Show less
Geloven, N. van; Balan, T.A.; Putter, H.; Cessie, S. le 2020
We study the effect of delaying treatment in the presence of (unobserved) heterogeneity. In a homogeneous population and assuming a proportional treatment effect, a treatment delay period will... Show moreWe study the effect of delaying treatment in the presence of (unobserved) heterogeneity. In a homogeneous population and assuming a proportional treatment effect, a treatment delay period will result in notably lower cumulative recovery percentages. We show in theoretical scenarios using frailty models that if the population is heterogeneous, the effect of a delay period is much smaller. This can be explained by the selection process that is induced by the frailty. Patient groups that start treatment later have already undergone more selection. The marginal hazard ratio for the treatment will act differently in such a more homogeneous patient group. We further discuss modeling approaches for estimating the effect of treatment delay in the presence of heterogeneity, and compare their performance in a simulation study. The conventional Cox model that fails to account for heterogeneity overestimates the effect of treatment delay. Including interaction terms between treatment and starting time of treatment or between treatment and follow up time gave no improvement. Estimating a frailty term can improve the estimation, but is sensitive to misspecification of the frailty distribution. Therefore, multiple frailty distributions should be used and the results should be compared using the Akaike Information Criterion. Non-parametric estimation of the cumulative recovery percentages can be considered if the dataset contains sufficient long term follow up for each of the delay strategies. The methods are demonstrated on a motivating application evaluating the effect of delaying the start of treatment with assisted reproductive techniques on time-to-pregnancy in couples with unexplained subfertility. Show less
