Search

01 januari 2023, Item does not contain fulltext, Statistical methods to test for effects of single nucleotide polymorphisms (SNPs) on exon inclusion exist but often rely on testing of associations between multiple exon-SNP pairs, with sometimes subsequent summarization of results at the gene level. Such approaches require heavy multiple testing corrections and detect mostly events with large effect sizes. We propose here a test to find spliceQTL (splicing quantitative trait loci) effects that takes all exons and all SNPs into account simultaneously. For any chosen gene, this score-based test looks for an association between the set of exon expressions and the set of SNPs, via a random-effects model framework. It is efficient to compute and can be used if the number of SNPs is larger than the number of samples. In addition, the test is powerful in detecting effects that are relatively small for individual exon-SNP pairs but are observed for many pairs. Furthermore, test results are more often replicated across datasets than pairwise testing results. This makes our test more robust to exon-SNP pair-specific effects, which do not extend to multiple pairs within the same gene. We conclude that the test we propose here offers more power and better replicability in the search for spliceQTL effects.

Radboud University, 20 april 2023, Promotor : Roes, C.B. Co-promotor : Jonker, M.A., Contains fulltext : 291366.pdf (Publisher’s version ) (Closed access)

Item does not contain fulltext, Malaria transmission depends on the presence of Plasmodium gametocytes that are the only parasite life stage that can infect mosquitoes. Gametocyte production varies between infections and over the course of infections. Infection duration is highly important for gametocyte production but poorly quantified. Between 2017 and 2019 an all-age cohort of individuals from Tororo, eastern Uganda was followed by continuous passive and routine assessments. We longitudinally monitored 104 incident infections from 98 individuals who were sampled once every 28 days and on any day of symptoms. Among infections that lasted ≥ 3 months, gametocyte appearance was near-universal with 96% of infections having detectable gametocytes prior to clearance. However, most infections were of much shorter duration; 55.7% of asymptomatic infections were detected only once. When considering all asymptomatic infections, regardless of their duration, only 36.3% had detectable gametocytes on at least one time-point prior to parasite clearance. Infections in individuals with sickle-cell trait (HbAS) were more likely to have gametocytes detected (Hazard Rate (HR) = 2.68, 95% CI 1.12, 6.38; p = 0.0231) and had gametocytes detected at higher densities (Density Ratio (DR) = 9.19, 95% CI 2.79, 30.23; p = 0.0002) compared to infections in wildtype (HbAA) individuals. Our findings suggest that a large proportion of incident infections is too short in duration and of too low density to contribute to onward transmission.

Item does not contain fulltext, AIM: Because the tyrosine kinases c-MET and vascular endothelial growth factor receptors (VEGFR) are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in patients with recurrent/metastatic (R/M) SGC. PATIENTS AND METHODS: A single-centre phase II study was conducted. Patients with immunohistochemical c-MET-positive R/M SGC were included in three cohorts: adenoid cystic carcinoma (ACC); salivary duct carcinoma (SDC) and other miscellaneous SGCs. No prior systemic treatments were required. Patients started cabozantinib 60 mg once daily. The primary outcome was the objective response rate (ORR). Secondary outcomes included survival, safety and quality of life. Per Simon-two-stage design, depending on efficacy, a maximum of 43 patients would be included. RESULTS: In total, 25 patients were included until premature closure owing to severe toxicity. Six patients (24%) had grade 3-5 wound complications, occurring at a median of 7.1 months on cabozantinib treatment (range 2.1-12.6). Remarkably, four of these six patients developed this complication in the area prior exposed to high-dose radiotherapy. Other grade ≥3 adverse events in >1 patient were hypertension (20%), diarrhoea (8%) and dehydration (8%). Twenty-one patients were evaluable for response; 1/15 ACC (ORR: 7%); 1/4 SDC and 0/2 patients with other miscellaneous SGC responded. Median progression-free survival was 9.4 months (95% confidence interval [CI] 7.4-11.4 months), 7.2 months (95%CI 0.0-15.1) and 6.9 months (95%CI 0.0-15.1), respectively. CONCLUSION: This study showed too many severe cabozantinib-associated wound complications in patients with SGC, especially in prior irradiated areas. Therefore, the study closed prematurely. The efficacy in the limited number of evaluable patients was low to moderate. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov: NCT03729297.

Contains fulltext : 283283.pdf (Publisher’s version ) (Closed access), In early phase clinical studies in oncology, Simon's two-stage designs are widely used. The trial design could be made more efficient by stopping early in the second stage when the required number of responses is reached, or when it has become clear that this target can no longer be met (a form of non-stochastic curtailment). Early stopping, however, will affect proper estimation of the response rate. We propose a uniformly minimum-variance unbiased estimator (UMVUE) for the response rate in this setting. The estimator is proven to be UMVUE using the Rao-Blackwell theorem. We evaluate the estimator's properties in terms of bias and mean squared error, both analytically and via simulations. We derive confidence intervals based on sample space orderings, and assess the coverage. For various design options, we evaluate the reduction in expected sample size as a function of the true response rate. Our method provides a solution for estimating response rates in case of a non-stochastic curtailment Simon's two-stage design.

Contains fulltext : 285308.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 286417.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 244316.pdf (Publisher’s version ) (Open Access), BACKGROUND: The BULLSEYE trial is a multicenter, open-label, randomized controlled trial to test the hypothesis if (177)Lu-PSMA is an effective treatment in oligometastatic hormone-sensitive prostate cancer (oHSPC) to prolong the progression-free survival (PFS) and postpone the need for androgen deprivation therapy (ADT). The original study protocol was published in 2020. Here, we report amendments that have been made to the study protocol since the commencement of the trial. CHANGES IN METHODS AND MATERIALS: Two important changes were made to the original protocol: (1) the study will now use (177)Lu-PSMA-617 instead of (177)Lu-PSMA-I&T and (2) responding patients with residual disease on (18)F-PSMA PET after the first two cycles are eligible to receive additional two cycles of 7.4 GBq (177)Lu-PSMA in weeks 12 and 18, summing up to a maximum of 4 cycles if indicated. Therefore, patients receiving (177)Lu-PSMA-617 will also receive an interim (18)F-PSMA PET scan in week 4 after cycle 2. The title of this study was modified to; "Lutetium-177-PSMA in Oligo-metastatic Hormone Sensitive Prostate Cancer" and is now partly supported by Advanced Accelerator Applications, a Novartis Company. CONCLUSIONS: We present an update of the original study protocol prior to the completion of the study. Treatment arm patients that were included and received (177)Lu-PSMA-I&T under the previous protocol will be replaced. TRIAL REGISTRATION: ClinicalTrials.gov NCT04443062 . First posted: June 23, 2020.

Contains fulltext : 230090.pdf (publisher's version ) (Open Access)

Item does not contain fulltext, Undiscovered gene-to-gene interaction (epistasis) is a possible explanation for the "missing heritability" of complex traits and diseases. On a genome-wide scale, screening for epistatic effects among all possible pairs of genetic markers faces two main complications. Firstly, the classical statistical methods for modeling epistasis are computationally very expensive, which makes them impractical on such large scale. Secondly, straightforward corrections for multiple testing using the classical methods tend to be too coarse and inefficient at discovering the epistatic effects in such a large scale application. In this chapter, we describe both the underlying framework and practical examples of two-stage statistical testing methods that alleviate both of the aforementioned complications.

Item does not contain fulltext

Contains fulltext : 236929.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 216650.pdf (publisher's version ) (Open Access)

Contains fulltext : 217766.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 225440.pdf (Publisher’s version ) (Open Access), Information on the age at onset distribution of the asymptomatic stage of a disease can be of paramount importance in early detection and timely management of that disease. However, accurately estimating this distribution is challenging, because the asymptomatic stage is difficult to recognize for the patient and is often detected as an incidental finding or in case of recommended screening; the age at onset is often interval-censored. In this paper, we propose a method for the estimation of the age at onset distribution of the asymptomatic stage of a genetic disease based on ascertained pedigree data that take into account the way the data are ascertained to overcome selection bias. Simulation studies show that the estimates seem to be asymptotically unbiased. Our work is motivated by the analysis of data on facioscapulohumeral muscular dystrophy, a genetic muscle disorder. In our application, carriers of the genetic causal variant are identified through genetic screening of the relatives of symptomatic carriers and their disease status is determined by a medical examination. The estimates reveal an early age at onset of the asymptomatic stage of facioscapulohumeral muscular dystrophy.

Contains fulltext : 225779.pdf (Publisher’s version ) (Open Access), AIM: The Observable Movement Quality (OMQ) scale measures generic movement quality and is used alongside standardized age-adequate motor performance tests. The scale consists of 15 items, each focusing on a different aspect; together, the entire construct of movement quality is assessed. This study aimed to determine interrater and intrarater reliability, and responsiveness of the OMQ scale. METHODS: A prospective intervention study with pre-post design in pediatric physical therapy practices. For interrater reliability, 3 physical therapists observed video-recorded motor assessments of 30 children with mild to moderate motor impairments -aged 4 to 12 years-using the OMQ scale. One therapist scored baseline assessment a second time for intrarater reliability, and to calculate smallest detectable change (SDC). Responsiveness (n = 28) was tested by comparing outcomes before and after intervention. RESULTS: Interrater reliability was moderate to good (ICC(2,1): 0.79); intrarater reliability was high (ICC(2,1): 0.97). Responsiveness results revealed an SDC of 2.4 and a minimal important change of 2.5; indicating sufficient validity in differentiating groups of children showing improved versus unchanged movement quality. CONCLUSION: The OMQ scale is reliable and responsive to change when used to assess movement quality in clinical practice for children with mild to moderate motor impairments, aged 4-12 year.

Contains fulltext : 218323.pdf (publisher's version ) (Open Access), BACKGROUND: Extracorporeally induced whole-body hyperthermia (eWBH) might be a beneficial treatment in cancer patients. Objectives of this pig study were to assess thermal distribution, (patho-)physiological effects, and safety of eWBH with a new WBH device. METHODS: Fourteen healthy adult pigs were anesthetized, mechanically ventilated, and cannulated; 12 were included in the analysis. Blood was heated in 11 pigs (one pig served as control) using a WBH device (Vither Hyperthermia B.V.) containing two separate fluidic circuits and a heat exchanger. Temperature was monitored on nine different sites, including the brain. Core temperature (average of 4 deep probes) was elevated to 42 degrees C for 2 hr. RESULTS: Elevation of core body temperature to 42 degrees C took on average (+/- standard deviation) 38 +/- 8 min. Initially observed temperature spikes diminished after lowering maximal blood temperature to 45 degrees C. Hereafter, brain temperature spikes never exceeded 42.5 degrees C, mean brain temperature was at highest 41.9 degrees C during maintenance. WBH resulted in increased heart rates and decreased mean arterial pressures. The vast amounts of fluids required to counter hypotension tended to be smaller after corticosteroid administration. Hemodialysis was started in three animals (potassium increase prevention in two and hyperkalemia treatment in one). Severe rhabdomyolysis was observed in all pigs (including the control). All animals survived the procedure until planned euthanasia 1, 6, or 24 hr post procedure. CONCLUSION: Fast induction of eWBH with homogenous thermal distribution is feasible in pigs using the Vither WBH device. Severe hemodynamic disturbances, rhabdomyolysis, and hyperkalemia were observed.

Contains fulltext : 224847.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 225057.pdf (publisher's version ) (Open Access), BACKGROUND: In recent years, there is increasing evidence showing a beneficial outcome (e.g. progression free survival; PFS) after metastases-directed therapy (MDT) with external beam radiotherapy (EBRT) or targeted surgery for oligometastatic hormone sensitive prostate cancer (oHSPC). However, many patients do not qualify for these treatments due to prior interventions or tumor location. Such oligometastatic patients could benefit from radioligand therapy (RLT) with (177)Lu-PSMA; a novel tumor targeting therapy for end-stage metastatic castration-resistant prostate cancer (mCRPC). Especially because RLT could be more effective in low volume disease, such as the oligometastatic status, due to high uptake of radioligands in smaller lesions. To test the hypothesis that (177)Lu-PSMA is an effective treatment in oHSPC to prolong PFS and postpone the need for androgen deprivation therapy (ADT), we initiated a multicenter randomized clinical trial. This is globally, the first prospective study using (177)Lu-PSMA-I&T in a randomized multicenter setting. METHODS & DESIGN: This study compares (177)Lu-PSMA-I&T MDT to the current standard of care (SOC); deferred ADT. Fifty-eight patients with oHSPC (≤5 metastases on PSMA PET) and high PSMA uptake (SUVmax > 15, partial volume corrected) on (18)F-PSMA PET after prior surgery and/or EBRT and a PSA doubling time of < 6 months, will be randomized in a 1:1 ratio. The patients randomized to the interventional arm will be eligible for two cycles of 7.4GBq (177)Lu-PSMA-I&T at a 6-week interval. After both cycles, patients are monitored every 3 weeks (including adverse events, QoL- and xerostomia questionnaires and laboratory testing) at the outpatient clinic. Twenty-four weeks after cycle two an end of study evaluation is planned together with another (18)F-PSMA PET and (whole body) MRI. Patients in the SOC arm are eligible to receive (177)Lu-PSMA-I&T after meeting the primary study objective, which is the fraction of patients who show

Contains fulltext : 220809.pdf (Publisher’s version ) (Open Access), BACKGROUND: Methotrexate in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) has limited progression-free survival (PFS) benefit. We hypothesized that adding cetuximab to methotrexate improves PFS. METHODS: In the phase-Ib-study, patients with R/M SCCHN received methotrexate and cetuximab as first-line treatment. The primary objective was feasibility. In the phase-II-study patients were randomized to this combination or methotrexate alone (2:1). The primary endpoint was PFS. Secondary endpoints were overall survival (OS), toxicity, and quality of life (QoL). RESULTS: In six patients in the phase-Ib-study, no dose limiting toxicities were observed. In the phase II study, 30 patients received the combination and 15 patients methotrexate. In the phase-II-study median PFS was 4.5 months in the combination group vs 2.0 months in the methotrexate group (HR 0.37; P = .002). OS, toxicity, and QoL were not significantly different. CONCLUSION: Cetuximab with methotrexate improved PFS without increased toxicity in R/M SCCHN-patients.

Contains fulltext : 228450.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 201168.pdf (publisher's version ) (Open Access)

Contains fulltext : 203702.pdf (publisher's version ) (Closed access)

Contains fulltext : 201751.pdf (publisher's version ) (Closed access)

Contains fulltext : 208801.pdf (publisher's version ) (Open Access), Accurate assessment of the age-dependent disease risk conferred by germline variants in disease susceptibility genes is often hampered by the way the data are collected. Cohort-based data sets frequently contain an overrepresentation of patients (i.e. carriers of the gene variant of interest affected with the associated disease), and an underrepresentation of disease-free carriers. In order to overcome this problem, penetrance estimates can be based on family-based study designs, through the evaluation of index patients and their family members. This approach facilitates the identification of asymptomatic germline variant carriers. By adjusting for the way these family data are ascertained, an estimate for the penetrance of the pathogenic gene variant can be obtained. However, the family structure is often incomplete or missing. This complicates the estimation of the penetrance, because full adjustment of the likelihood is not possible. We present a conditional likelihood for the estimation of the penetrance of pathogenic gene variants, based on a cohort of multiple families comprising index patients, disease-free and affected non-index carriers, but with missing information on pedigree structure. The proposed estimator corrects for the ascertainment in a robust way and is shown to be more accurate than the frequently used Kaplan-Meier estimator of the penetrance function.

Contains fulltext : 202130.pdf (publisher's version ) (Open Access)

Contains fulltext : 206246.pdf (publisher's version ) (Open Access)

Contains fulltext : 202493.pdf (publisher's version ) (Open Access)

Item does not contain fulltext

Item does not contain fulltext, OBJECTIVE: To investigate the effectiveness of Energetic, a self-management group program combining aerobic training, energy conservation management, and relapse prevention to improve social participation in patients with neuromuscular disease (NMD) and chronic fatigue. METHODS: In this multicenter, assessor-blinded, 2-armed randomized controlled trial with repeated measurements, 53 patients with various types of NMD and chronic fatigue were randomly allocated to Energetic, a 4-month group intervention, or to usual care. The primary endpoint was social participation assessed with the Canadian Occupational Performance Measure (COPM) performance scale immediately postintervention. Secondary outcomes included COPM satisfaction scale, 6-Minute Walk Test (6MWT), and Checklist Individual Strength-subscale fatigue. Participants were followed for 11 months postintervention. Data were analyzed with linear models that account for repeated measurements. RESULTS: Directly after intervention, the mean group difference for COPM-performance was 1.7 (95% confidence interval [CI] 1.0-2.4; p < 0.0001) in favor of the intervention group (n = 29), adjusted for baseline, sex, diagnosis, and work status. This effect was retained at 11 months follow-up (0.9; 95% CI 0.0-1.7; p = 0.049). The COPM satisfaction scale and 6MWT improved more in the intervention group compared to usual care. After 3 and 11 months follow-up, most beneficial effects on social participation and functional endurance were retained. CONCLUSION: Energetic led to sustainable improvements in social participation and functional endurance compared to usual care in patients with NMD and chronic fatigue.Clinicaltrials.gov IDENTIFIER: NCT02208687. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a combination of aerobic training, energy conservation management, and relapse prevention improves social participation in patients with NMD and chronic fatigue.

Contains fulltext : 181372.pdf (publisher's version ) (Open Access)

Contains fulltext : 190740.pdf (Publisher’s version ) (Open Access), BACKGROUND AND PURPOSE: Precise in vivo measurement of deep GM volume change is a highly demanded prerequisite for an adequate evaluation of disease progression and new treatments. However, quantitative data on the reproducibility of deep GM structure volumetry are not yet available. In this paper we aim to investigate this reproducibility using a large multicenter dataset. MATERIALS AND METHODS: We have assessed the reproducibility of 2 automated segmentation software packages (FreeSurfer and the FMRIB Integrated Registration and Segmentation Tool) by quantifying the volume changes of deep GM structures by using back-to-back MR imaging scans from the Alzheimer Disease Neuroimaging Initiative's multicenter dataset. Five hundred sixty-two subjects with scans at baseline and 1 year were included. Reproducibility was investigated in the bilateral caudate nucleus, putamen, amygdala, globus pallidus, and thalamus by carrying out descriptives as well as multilevel and variance component analysis. RESULTS: Median absolute back-to-back differences varied between GM structures, ranging from 59.6-156.4 muL for volume change, and 1.26%-8.63% for percentage volume change. FreeSurfer had a better performance for the outcome of longitudinal volume change for the bilateral amygdala, putamen, left caudate nucleus (P < .005), and right thalamus (P < .001). For longitudinal percentage volume change, Freesurfer performed better for the left amygdala, bilateral caudate nucleus, and left putamen (P < .001). Smaller limits of agreement were found for FreeSurfer for both outcomes for all GM structures except the globus pallidus. Our results showed that back-to-back differences in 1-year percentage volume change were approximately 1.5-3.5 times larger than the mean measured 1-year volume change of those structures. CONCLUSIONS: Longitudinal deep GM atrophy measures should be interpreted with caution. Furthermore, deep GM atrophy measurement techniques require substantially improved reprodu

Item does not contain fulltext

Item does not contain fulltext

Contains fulltext : 183945.pdf (publisher's version ) (Open Access)

Item does not contain fulltext

Salivary duct carcinoma (SDC) is a subtype of salivary gland cancer with a dismal prognosis and a need for better prognostication and novel treatments. The aim of this national cohort study was to investigate clinical outcome, prognostic factors, androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2) expression. SDC patients diagnosed between 1990 and 2014 were identified by the Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands (PALGA). Subsequently, medical records were evaluated and pathological diagnoses reviewed. Data were analyzed for overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and prognostic factors. AR was evaluated by immunohistochemistry (IHC), HER2 by IHC and fluorescent in-situ hybridization. A total of 177 patients were included. The median age was 65 years, 75% were male. At diagnosis, 68% presented with lymph node metastases and 6% with distant metastases. Median OS, DFS and DMFS were 51, 23 and 26 months, respectively. In patients presenting without distant metastases, the absolute number of positive lymph nodes was associated with poor OS and DMFS in a multivariable analysis. AR and HER2 were positive in 161/168 (96%) and 44/153 (29%) tumors, respectively, and were not prognostic factors. SDC has a dismal prognosis with primary lymph node involvement in the majority of patients. The absolute number of lymph node metastases was found to be the only prognostic factor for DMFS and OS. AR expression and-to a lesser extent-HER2 expression hold promise for systemic treatment in the metastatic and eventually adjuvant setting.

Contains fulltext : 198339.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext