ObjectiveTo evaluate clinical, audiological and neuroimaging findings in a cohort of infants diagnosed with congenital cytomegalovirus (cCMV) infection after failure at newborn hearing screening.... Show moreObjectiveTo evaluate clinical, audiological and neuroimaging findings in a cohort of infants diagnosed with congenital cytomegalovirus (cCMV) infection after failure at newborn hearing screening. MethodsA prospective observational study in the Netherlands, using the existing newborn hearing screening infrastructure for well babies. Between July 2012 and November 2016, cytomegalovirus (CMV) PCR testing of neonatally obtained dried blood spots (DBS) was offered to all infants who failed newborn hearing screening. Clinical, neuroimaging and audiological data were collected. ResultsDBS of 1374 infants were successfully tested and 59 were positive for CMV (4.3%). Data of 54 infants were retrieved. Three were small for gestational age and six had microcephaly. Forty-eight (89%) had sensorineural hearing loss (SNHL), of whom half had unilateral SNHL. In both unilaterally and bilaterally affected children, the majority of the impaired ears had severe or profound hearing loss. Neuroimaging abnormalities were found in 40 of 48 (83%) children who had evaluable cranial ultrasound and/or cerebral MRI. The abnormalities were mild in 34, moderate in 3 and severe in 3 infants. The degree of SNHL and the severity of neuroimaging abnormalities were found to be correlated (p=0.002). ConclusionsThe yield of targeted cCMV screening following newborn hearing screening failure was eight times higher than the estimated national birth prevalence of cCMV. The majority of this cohort of infants with clinically unsuspected cCMV disease had confirmed SNHL, neuroimaging abnormalities and lower than average birth weights and head circumferences. Newborns who fail newborn hearing screening should be tested for CMV to ensure appropriate clinical, neurodevelopmental and audiological follow-up. Show less
OBJECTIVE: Interspinous process distraction devices (IPDs) can be implanted to treat patients with intermittent neurogenic claudication (INC) due to lumbar spinal stenosis. Short-term results... Show moreOBJECTIVE: Interspinous process distraction devices (IPDs) can be implanted to treat patients with intermittent neurogenic claudication (INC) due to lumbar spinal stenosis. Short-term results provided evidence that the outcomes of IPD implantation were comparable to those of decompressive surgery, although the reoperation rate was higher in patients who received an IPD. This study focuses on the long-term results. METHODS: Patients with INC and spinal stenosis at 1 or 2 levels randomly underwent either decompression or IPD implantation. Patients were blinded to the allocated treatment. The primary outcome was the Zurich Claudication Questionnaire (ZCQ) score at 5-year follow-up. Repeated measurement analysis was applied to compare outcomes over time. RESULTS: In total, 159 patients were included and randomly underwent treatment: 80 patients were randomly assigned to undergo IPD implantation, and 79 underwent spinal bony decompression. At 5 years, the success rates in terms of ZCQ score were similar (68% of patients who underwent IPD implantation had a successful recovery vs 56% of those who underwent bony decompression, p = 0.422). The reoperation rate at 2 years after surgery was substantial in the IPD group (29%), but no reoperations were performed thereafter. Long-term visual analog scale score for back pain was lower in the IPD group than the bony decompression group (p = 0.02). CONCLUSIONS: IPD implantation is a more expensive alternative to decompressive surgery for INC but has comparable functional outcome during follow-up. The risk of reoperation due to absence of recovery is substantial in the first 2 years after IPD implantation, but if surgery is successful this positive effect remains throughout long-term follow-up. The IPD group had less back pain during long-term follow-up, but the clinical relevance of this finding is debatable. Dutch Trial Register no.: NTR1307 https://thejns.org/doi/abs/10.3171/2021.8.SPINE21419 Show less
Raven, W.; Hoven, E.M.P. van den; Gaakeer, M.I.; Avest, E. ter; Sir, O.; Lameijer, H.; ... ; Groot, B. de 2022
Background and importance Although aging societies in Western Europe use presenting complaints (PCs) in emergency departments (EDs) triage systems to determine the urgency and severity of the care... Show moreBackground and importance Although aging societies in Western Europe use presenting complaints (PCs) in emergency departments (EDs) triage systems to determine the urgency and severity of the care demand, it is unclear whether their prognostic value is age-dependent.Objective To assess the frequency and association of PCs with hospitalization and mortality across age categories.Methods An observational multicenter study using all consecutive visits of three EDs in the Netherlands Emergency department Evaluation Database. Patients were stratified by age category (0-18; 19-50; 51-65; 66-80; >80 years), in which the association between PCs and case-mix adjusted hospitalization and mortality was studied using multivariable logistic regression analysis (adjusting for demographics, hospital, disease severity, comorbidity and other PCs)Results We included 172 104 ED-visits. The most frequent PCs were 'extremity problems' [range across age categories (13.5-40.8%)], 'feeling unwell' (9.5-23.4%), 'abdominal pain' (6.0-13.9%), 'dyspnea' (4.5-13.3%) and 'chest pain' (0.6-10.7%). For most PCs, the observed and the case-mix-adjusted odds for hospitalization and mortality increased the higher the age category. The most common PCs with the highest adjusted odds ratios (AORs, 95% CI) for hospitalization were 'diarrhea and vomiting' [2.30 (2.02-2.62)] and 'feeling unwell' [1.60 (1.48-1.73)]. Low hospitalization risk was found for 'chest pain' [0.58 (0.53-0.63)] and `palpitations' [0.64 (0.58-0.71)].Conclusions Frequency of PCs in ED patients varies with age, but the same PCs occur in all age categories. For most PCs, (case-mix adjusted) hospitalization and mortality vary across age categories. 'Chest pain' and 'palpitations,' usually triaged 'very urgent', carry a low risk for hospitalization and mortality. European Journal of Emergency Medicine 29: 33-41 Copyright (c) 2021 Wolters Kluwer Health, Inc. All rights reserved. Show less
Candel, B.G.J.; Khoudja, J.; Gaakeer, M.I.; Avest, E. ter; Sir, O.; Lameijer, H.; ... ; Groot, B. de 2022
Appropriate interpretation of blood tests is important for risk stratification and guidelines used in the Emergency Department (ED) (such as SIRS or CURB-65). The impact of abnormal blood test... Show moreAppropriate interpretation of blood tests is important for risk stratification and guidelines used in the Emergency Department (ED) (such as SIRS or CURB-65). The impact of abnormal blood test values on mortality may change with increasing age due to (patho)-physiologic changes. The aim of this study was therefore to assess the effect of age on the case-mix adjusted association between biomarkers of renal function and homeostasis, inflammation and circulation and in-hospital mortality. This observational multi-center cohort study has used the Netherlands Emergency department Evaluation Database (NEED), including all consecutive ED patients >= 18 years of three hospitals. A generalized additive logistic regression model was used to visualize the association between in-hospital mortality, age and five blood tests (creatinine, sodium, leukocytes, C-reactive Protein, and hemoglobin). Multivariable logistic regression analyses were used to assess the association between the number of abnormal blood test values and mortality per age category (18-50; 51-65; 66-80; > 80 years). Of the 94,974 included patients, 2550 (2.7%) patients died in-hospital. Mortality increased gradually for C-reactive Protein (CRP), and had a U-shaped association for creatinine, sodium, leukocytes, and hemoglobin. Age significantly affected the associations of all studied blood tests except in leukocytes. In addition, with increasing age categories, case-mix adjusted mortality increased with the number of abnormal blood tests. In summary, the association between blood tests and (adjusted) mortality depends on age. Mortality increases gradually or in a U-shaped manner with increasing blood test values. Age-adjusted numerical scores may improve risk stratification. Our results have implications for interpretation of blood tests and their use in risk stratification tools and acute care guidelines. Show less
Background: Traumatic brain injury (TBI) is a major cause of death and disability across all ages. After the primary impact, the pathophysiologic process of secondary brain injury consists of a... Show moreBackground: Traumatic brain injury (TBI) is a major cause of death and disability across all ages. After the primary impact, the pathophysiologic process of secondary brain injury consists of a neuroinflammation response that critically leads to irreversible brain damage in the first days after the trauma. A key catalyst in this inflammatory process is the complement system. Inhibiting the complement system could therefore be a therapeutic target in TBI.Objective: To study the safety and efficacy of C1-inhibitor (C1-INH) compared to placebo in patients with TBI. By temporarily blocking the complement system, we hypothesize a decrease in the posttraumatic neuroinflammatory response resulting in a less unfavorable clinical outcome for TBI patients.Methods: CIAO@TBI is a multicenter, randomized, blinded, phase II placebo-controlled trial. Adult TBI patients with GCS < 13 requiring intracranial pressure (ICP) monitoring will be randomized, using block randomization, within 12 h after trauma to one dose 6000 IU C1-INH or placebo. A total of 106 patients will be included, and follow-up will occur up to 12 months. The primary endpoints are (1) Therapy Intensity Level (TIL) Scale, (2) Glasgow Outcome Scale-Extended (GOSE) at 6 months, and (3) complication rate during hospitalization. Outcomes will be determined by a trial nurse blinded for the treatment allocation. Analyses will be conducted in an intention-to-treat analysis.Discussion: We expect that C1-INH administration will be safe and potentially effective to improve clinical outcomes by reducing neuroinflammation in TBI patients. Show less
We abstract the concept of a randomized controlled trial as a triple (beta,b,s), where beta is the primary efficacy parameter, b the estimate, and s the standard error (s>0). If the parameter... Show moreWe abstract the concept of a randomized controlled trial as a triple (beta,b,s), where beta is the primary efficacy parameter, b the estimate, and s the standard error (s>0). If the parameter beta is either a difference of means, a log odds ratio or a log hazard ratio, then it is reasonable to assume that b is unbiased and normally distributed. This then allows us to estimate the joint distribution of the z-value z=b/s and the signal-to-noise ratio SNR=beta/s from a sample of pairs (bi,si). We have collected 23 551 such pairs from the Cochrane database. We note that there are many statistical quantities that depend on (beta,b,s) only through the pair (z,SNR). We start by determining the estimated distribution of the achieved power. In particular, we estimate the median achieved power to be only 13%. We also consider the exaggeration ratio which is the factor by which the magnitude of beta is overestimated. We find that if the estimate is just significant at the 5% level, we would expect it to overestimate the true effect by a factor of 1.7. This exaggeration is sometimes referred to as the winner's curse and it is undoubtedly to a considerable extent responsible for disappointing replication results. For this reason, we believe it is important to shrink the unbiased estimator, and we propose a method for doing so. We show that our shrinkage estimator successfully addresses the exaggeration. As an example, we re-analyze the ANDROMEDA-SHOCK trial. Show less
Sprenger, G.P.; Roos, R.A.C.; Zwet, E. van; Reijntjes, R.H.; Achterberg, W.P.; Bot, S.T. de 2021
Introduction: Pain could be an unknown non-motor symptom in Huntington's Disease (HD). The aim is therefore, to study the prevalence of pain interference, painful conditions and analgesic use... Show moreIntroduction: Pain could be an unknown non-motor symptom in Huntington's Disease (HD). The aim is therefore, to study the prevalence of pain interference, painful conditions and analgesic use across the different stages of HD and compare these levels to non-HD gene mutation carriers.Methods: A cross-sectional analysis of the Enroll-HD study was conducted in premanifest, manifest HD gene mutation carriers (n = 3989 and n = 7,485, respectively) and in non-HD gene mutation carriers (n = 3719). To investigate group differences, multivariable logistic regression analysis was performed with pairwise comparisons.Results: In the HD mutation carriers, the overall prevalence of pain interference was 34% (95% CI 31%-35%), of painful conditions 17% (95% CI 15%-19%) and analgesic use 13% (95% CI 11%-15%). Compared to non-mutation carriers, the prevalence of pain interference was significantly higher in the middle stage of HD (33% [95% CI 31%-35%] vs 42% [95% CI 39%-45%], P = 0,02), whereas the prevalence of painful conditions was significant lower in the late and middle stage of HD (17% [95% CI 16%-18%] vs 12% [95% CI 10%-14%], 15% [95% CI 13%-17%], P < 0,01]. No significant group difference was present in analgesic use.Conclusions: The prevalence of pain interference increases as HD progresses, however, the prevalence of painful conditions and analgesics do not increase accordingly. Further studies are necessary to investigate the aetiology of pain in HD and the risk for undertreatment of pain. Show less
Sprenger, G.P.; Roos, R.A.C.; Zwet, E. van; Reijntjes, R.H.; Achterberg, W.P.; Bot, S.T. de 2021
Introduction: Pain could be an unknown non-motor symptom in Huntington's Disease (HD). The aim is therefore, to study the prevalence of pain interference, painful conditions and analgesic use... Show moreIntroduction: Pain could be an unknown non-motor symptom in Huntington's Disease (HD). The aim is therefore, to study the prevalence of pain interference, painful conditions and analgesic use across the different stages of HD and compare these levels to non-HD gene mutation carriers.Methods: A cross-sectional analysis of the Enroll-HD study was conducted in premanifest, manifest HD gene mutation carriers (n = 3989 and n = 7,485, respectively) and in non-HD gene mutation carriers (n = 3719). To investigate group differences, multivariable logistic regression analysis was performed with pairwise comparisons.Results: In the HD mutation carriers, the overall prevalence of pain interference was 34% (95% CI 31%-35%), of painful conditions 17% (95% CI 15%-19%) and analgesic use 13% (95% CI 11%-15%). Compared to non-mutation carriers, the prevalence of pain interference was significantly higher in the middle stage of HD (33% [95% CI 31%-35%] vs 42% [95% CI 39%-45%], P = 0,02), whereas the prevalence of painful conditions was significant lower in the late and middle stage of HD (17% [95% CI 16%-18%] vs 12% [95% CI 10%-14%], 15% [95% CI 13%-17%], P < 0,01]. No significant group difference was present in analgesic use.Conclusions: The prevalence of pain interference increases as HD progresses, however, the prevalence of painful conditions and analgesics do not increase accordingly. Further studies are necessary to investigate the aetiology of pain in HD and the risk for undertreatment of pain. Show less
Objective: to obtain locally valid reference values (RVs) from existing nerve conduction study (NCS) data.Methods: we used age, sex, height and limb temperature-based mixture model clustering (MMC)... Show moreObjective: to obtain locally valid reference values (RVs) from existing nerve conduction study (NCS) data.Methods: we used age, sex, height and limb temperature-based mixture model clustering (MMC) to identify normal and abnormal measurements on NCS data from two university hospitals. We compared MMC-derived RVs to published data; examined the effect of using different variables; validated MMC-derived RVs using independent data from 26 healthy control subjects and investigated their clinical applicability for the diagnosis of polyneuropathy.Results: MMC-derived RVs were similar to published RVs. Clustering can be achieved using only sex and age as variables. MMC is likely to yield reliable results with fewer abnormal than normal measurements and when the total number of measurements is at least 300. Measurements from healthy controls fell within the 95% MMC-derived prediction interval in 97.4% of cases.Conclusions: MMC can be used to obtain RVs from existing data, providing a locally valid, accurate reflection of the (ab)normality of an NCS result.Significance: MMC can be used to generate locally valid RVs for any test for which sufficient data are available.(1) (C) 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. Show less
If we have an unbiased estimate of some parameter of interest, then its absolute value is positively biased for the absolute value of the parameter. This bias is large when the signal-to-noise... Show moreIf we have an unbiased estimate of some parameter of interest, then its absolute value is positively biased for the absolute value of the parameter. This bias is large when the signal-to-noise ratio (SNR) is small, and it becomes even larger when we condition on statistical significance; the winner's curse. This is a frequentist motivation for regularization or "shrinkage." To determine a suitable amount of shrinkage, we propose to estimate the distribution of the SNR from a large collection or "corpus" of similar studies and use this as a prior distribution. The wider the scope of the corpus, the less informative the prior, but a wider scope does not necessarily result in a more diffuse prior. We show that the estimation of the prior simplifies if we require that posterior inference is equivariant under linear transformations of the data. We demonstrate our approach with corpora of 86 replication studies from psychology and 178 phase 3 clinical trials. Our suggestion is not intended to be a replacement for a prior based on full information about a particular problem; rather, it represents a familywise choice that should yield better long-term properties than the current default uniform prior, which has led to systematic overestimates of effect sizes and a replication crisis when these inflated estimates have not shown up in later studies. Show less
Background and Purpose:Cortical calcifications have been reported in patients with cerebral amyloid angiopathy (CAA), although their prevalence and pathophysiology are unknown. We investigated the... Show moreBackground and Purpose:Cortical calcifications have been reported in patients with cerebral amyloid angiopathy (CAA), although their prevalence and pathophysiology are unknown. We investigated the frequency of calcifications on computed tomography, their association with intracerebral hemorrhage (ICH) and their coexistence with a striped pattern of the occipital cortex reflecting microcalcifications on ultra-high-field 7T-magnetic resonance imaging in Dutch-type hereditary CAA (D-CAA) and sporadic CAA.Methods:We included D-CAA mutation carriers with a proven APP (amyloid precursor protein) mutation or >= 1 lobar ICH and >= 1 first-degree relative with D-CAA and sporadic CAA patients with probable CAA according to the modified Boston criteria. D-CAA carriers were regarded symptomatic when they had a history of symptomatic ICH. We assessed the presence, location, and progression of calcifications and their association with ICH and the striped occipital cortex.Results:We found cortical calcifications in 15/81 (19% [95% CI, 11-29]) D-CAA mutation carriers (15/69 symptomatic and 0/12 presymptomatic) and in 1/59 (2% [95% CI, 0-9]) sporadic CAA patients. Calcifications were all bilateral located in the occipital lobes. In 3/15 (20%) of the symptomatic D-CAA patients the calcifications progressed over a period up to 10 years. There was evidence of an association between cortical calcifications and new ICH development (hazard ratio, 7.1 [95% CI, 0.9-54.9], log-rank P=0.03). In 7/25 D-CAA symptomatic carriers in whom a 7T-magnetic resonance imaging was performed, a striped pattern of the occipital cortex was present; in 3/3 (100%) of those with calcifications on computed tomography and 4/22 (18%) of those without calcifications.Conclusions:Occipital cortical calcifications are frequent in D-CAA but seem to be rare in sporadic CAA. Their absence in presymptomatic carriers and their association with ICH might suggest that they are a marker for advanced CAA. Cortical calcifications on computed tomography seem to be associated with the striped occipital cortex on 7T-magnetic resonance imaging which may possibly represent an early stage of calcification. Show less
Sewalt, C.A.; Venema, E.; Zwet, E. van; Ditshuizen, J.C. van; Schuit, S.C.E.; Polinder, S.; ... ; LTR Res Grp 2021
Centralization of trauma centers leads to a higher hospital volume of severely injured patients (Injury Severity Score (ISS) > 15), but the effect of volume on outcome remains unclear. The aim... Show moreCentralization of trauma centers leads to a higher hospital volume of severely injured patients (Injury Severity Score (ISS) > 15), but the effect of volume on outcome remains unclear. The aim of this study was to determine the association between hospital volume of severely injured patients and in-hospital mortality in Dutch Level-1 trauma centers. A retrospective observational cohort study was performed using the Dutch trauma registry. All severely injured adults (ISS > 15) admitted to a Level-1 trauma center between 2015 and 2018 were included. The effect of hospital volume on in-hospital mortality was analyzed with random effects logistic regression models with a random intercept for Level-1 trauma center, adjusted for important demographic and injury characteristics. A total of 11,917 severely injured patients from 13 Dutch Level-1 trauma centers was included in this study. Hospital volume varied from 120 to 410 severely injured patients per year. Observed mortality rates varied between 12% and 24% per center. After case-mix correction, no statistically significant differences between low- and high-volume centers were demonstrated (adjusted odds ratio 0.97 per 50 extra patients per year, 95% Confidence Interval 0.90-1.04, p = 0.44). The variation in hospital volume of the included Level-1 trauma centers was not associated with the outcome of severely injured patients. Our results suggest that well-organized trauma centers with a similar organization of care could potentially achieve comparable outcomes. Show less
Mohamad, D. al; Zwet, E. van; Solari, A.; Goeman, J. 2021
We consider the problem of constructing simultaneous confidence intervals (CIs) for the ranks of n means based on their estimates together with the (known) standard errors of those estimates. We... Show moreWe consider the problem of constructing simultaneous confidence intervals (CIs) for the ranks of n means based on their estimates together with the (known) standard errors of those estimates. We present a generic method based on the partitioning principle in which the parameter space is partitioned into disjoint subsets and then each one of them is tested at level a. The resulting CIs have then a simultaneous coverage of 1 - alpha. We show that any procedure which produces simultaneous CIs for ranks can be written as a partitioning procedure. We present a first example where we test the partitions using the likelihood ratio (LR) test. Then, in a second example we show that a recently proposed method for simultaneous CIs for ranks using Tukey's honest significant difference test has an equivalent procedure based on the partitioning principle. By embedding these two methods inside our generic partitioning procedure, we obtain improved variants. We illustrate the performance of these methods through simulations and real data analysis on hotel ratings. While the novel method that uses the LR test and its variant produce shorter CIs when the number of means is small, the Tukey-based method and its variant produce shorter CIs when the number of means is high. Show less
Kuhrij, L.; Zwet, E. van; Berg-Vos, R. van den; Nederkoorn, P.; Marang-van de Mheen, P.J. 2021
Background Hospitals and providers receive feedback information on how their performance compares with others, often using funnel plots to detect outliers. These funnel plots typically use binary... Show moreBackground Hospitals and providers receive feedback information on how their performance compares with others, often using funnel plots to detect outliers. These funnel plots typically use binary outcomes, and continuous variables are dichotomised to fit this format. However, information is lost using a binary measure, which is only sensitive to detect differences in higher values (the tail) rather than the entire distribution. This study therefore aims to investigate whether different outlier hospitals are identified when using a funnel plot for a binary vs a continuous outcome. This is relevant for hospitals with suboptimal performance to decide whether performance can be improved by targeting processes for all patients or a subgroup with higher values.Methods We examined the door-to-needle time (DNT) of all (6080) patients with acute ischaemic stroke treated with intravenous thrombolysis in 65 hospitals in 2017, registered in the Dutch Acute Stroke Audit. We compared outlier hospitals in two funnel plots: the median DNT versus the proportion of patients with substantially delayed DNT (above the 90th percentile (P90)), whether these were the same or different hospitals. Two sensitivity analyses were performed using the proportion above the median and a continuous P90 funnel plot.Results The median DNT was 24 min and P90 was 50 min. In the binary funnel plot for the proportion of patients above P90, 58 hospitals had average performance, whereas in the funnel plot around the median 14 of these hospitals had significantly higher median DNT (24%). These hospitals can likely improve their DNT by focusing on care processes for all patients, not shown by the binary outcome funnel plot. Similar results were shown in sensitivity analyses.Conclusion Using funnel plots for continuous versus binary outcomes identify different outlier hospitals, which may enhance hospital feedback to direct more targeted improvement initiatives. Show less
OBJECTIVE The most advocated surgical technique to treat symptoms of isthmic spondylolisthesis is decompression with instrumented fusion. A less-invasive classical approach has also been reported,... Show moreOBJECTIVE The most advocated surgical technique to treat symptoms of isthmic spondylolisthesis is decompression with instrumented fusion. A less-invasive classical approach has also been reported, which consists of decompression only. In this study the authors compared the clinical outcomes of decompression only with those of decompression with instrumented fusion in patients with isthmic spondylolisthesis. METHODS Eighty-four patients with lumbar radiculopathy or neurogenic claudication secondary to low-grade isthmic spondylolisthesis were randomly assigned to decompression only (n = 43) or decompression with instrumented fusion (n = 41). Primary outcome parameters were scores on the Roland Disability Questionnaire (RDQ), separate visual analog scales (VASs) for back pain and leg pain, and patient report of perceived recovery at 12-week and 2-year follow-ups. The proportion of reoperations was scored as a secondary outcome measure. Repeated measures ANOVA according to the intention-to-treat principle was performed. RESULTS Decompression alone did not show superiority in terms of disability scores at 12-week follow-up (p = 0.32, 95% CI -4.02 to 1.34), nor in any other outcome measure. At 2-year follow-up, RDQ disability scores improved more in the fusion group (10.3, 95% CI 3.9-8.2, vs 6.0, 95% CI 8.2-12.4; p = 0.006, 95% CI -7.3 to -1.3). Likewise, back pain decreased more in the fusion group (difference: -18.3 mm, CI -32.1 to -4.4, p = 0.01) on a 100-mm VAS scale, and a higher proportion of patients perceived recovery as showing "good results" (44% vs 74%, p = 0.01). Cumulative probabilities for reoperation were 47% in the decompression and 13% in the fusion group (p < 0.001) at the 2-year follow-up. CONCLUSIONS In patients with isthmic spondylolisthesis, decompression with instrumented fusion resulted in comparable short-term results, significantly better long-term outcomes, and fewer reoperations than decompression alone. Decompression with instrumented fusion is a superior surgical technique that should in general be offered as a first treatment option for isthmic spondylolisthesis, but not for degenerative spondylolisthesis, which has a different etiology. Clinical trial registration number: NTR1300 (Netherlands Trial Register) Show less
Objectives Pharmacogenetic panel-based testing represents a new model for precision medicine. A sufficiently powered prospective study assessing the (cost-)effectiveness of a panel-based... Show moreObjectives Pharmacogenetic panel-based testing represents a new model for precision medicine. A sufficiently powered prospective study assessing the (cost-)effectiveness of a panel-based pharmacogenomics approach to guide pharmacotherapy is lacking. Therefore, the Ubiquitous Pharmacogenomics Consortium initiated the PREemptive Pharmacogenomic testing for prevention of Adverse drug Reactions (PREPARE) study. Here, we provide an overview of considerations made to mitigate multiple methodological challenges that emerged during the design. Methods An evaluation of considerations made when designing the PREPARE study across six domains: study aims and design, primary endpoint definition and collection of adverse drug events, inclusion and exclusion criteria, target population, pharmacogenomics intervention strategy, and statistical analyses. Results Challenges and respective solutions included: (1) defining and operationalizing a composite primary endpoint enabling measurement of the anticipated effect, by including only severe, causal, and drug genotype-associated adverse drug reactions; (2) avoiding overrepresentation of frequently prescribed drugs within the patient sample while maintaining external validity, by capping drugs of enrolment; (3) designing the pharmacogenomics intervention strategy to be applicable across ethnicities and healthcare settings; and (4) designing a statistical analysis plan to avoid dilution of effect by initially excluding patients without a gene-drug interaction in a gatekeeping analysis. Conclusion Our design considerations will enable quantification of the collective clinical utility of a panel of pharmacogenomics-markers within one trial as a proof-of-concept for pharmacogenomics-guided pharmacotherapy across multiple actionable gene-drug interactions. These considerations may prove useful to other investigators aiming to generate evidence for precision medicine. Show less
Snowden, J.A.; Saccardi, R.; Orchard, K.; Ljungman, P.; Duarte, R.F.; Labopin, M.; ... ; Putter, H. 2020
In many healthcare settings, benchmarking for complex procedures has become a mandatory requirement by competent authorities, regulators, payers and patients to assure clinical performance, cost... Show moreIn many healthcare settings, benchmarking for complex procedures has become a mandatory requirement by competent authorities, regulators, payers and patients to assure clinical performance, cost-effectiveness and safe care of patients. In several countries inside and outside Europe, benchmarking systems have been established for haematopoietic stem cell transplantation (HSCT), but access is not universal. As benchmarking is now integrated into the FACT-JACIE standards, the EBMT and JACIE established a Clinical Outcomes Group (COG) to develop and introduce a universal system accessible across EBMT members. Established systems from seven European countries (United Kingdom, Italy, Belgium, France, Germany, Spain, Switzerland), USA and Australia were appraised, revealing similarities in process, but wide variations in selection criteria and statistical methods. In tandem, the COG developed the first phase of a bespoke risk-adapted international benchmarking model for one-year survival following allogeneic and autologous HSCT based on current capabilities within the EBMT registry core dataset. Data completeness, which has a critical impact on validity of centre comparisons, is also assessed. Ongoing development will include further scientific validation of the model, incorporation of further variables (when appropriate) alongside implementation of systems for clinically meaningful interpretation and governance aiming to maximise acceptance to centres, clinicians, payers and patients across EBMT. Show less
