Evidence from clinical practice to support healthcare decision making

The growing pressure on healthcare budgets creates great tension between financial sustainability of healthcare systems and accessibility to (new) treat¬ments. To ensure equal and timely access to promising but costly inpatient drugs, conditional funding was introduced in the Netherlands in 2006. At that time, conditional funding implied the additional funding of innovative drugs (i.e. reimbursing hospitals [most of] the drug costs) for a period of three years on the condition that data regarding uptake, use and outcomes (in terms of effectiveness and cost-effectiveness) of these drugs in clinical practice were to be collected. Conditional funding applied to two innovative but costly drugs for patients with metastatic renal cell carcinoma, i.e. bevacizumab and temsirolimus. This dissertation shows that the traditional treatment with interferon-alpha (IFN-α) has been largely replaced by treatment with so-called targeted therapies, mainly sunitinib. It also shows that few patients were treated with bevacizumab (in combination with IFN-α) or temsirolimus, even though these therapies were added to European guidelines in 2009, and Dutch guidelines in 2010 (besides sunitinib). Due to the limited use of bevacizumab and temsirolimus in clinical practice, data collection yielded little additional evidence regarding the effectiveness and cost-effectiveness of these drugs. This dissertation did show that new therapies that prolong progression-free survival (as demonstrated in other studies), postpone reductions in health-related quality of life. This is because symptoms, such as fatigue and pain, increase with progression of disease. In addition, the dissertation showed that the overall mix of new drugs has led to an increase in quality-adjusted life-years of patients with metastatic renal cell carcinoma, as well as an increase in costs. In line with the current policy of so-called specialist drugs (including costly inpatient and outpatient drugs), this dissertation states to restrict the use of conditional funding of expensive drugs. Only in specific cases is outcomes research able to provide a more robust estimate of cost-effectiveness. These cases should be selected carefully in order to minimize the costs of extensive data collection

Investigating selection on viruses: a statistical alignment approach

<p>Abstract</p> <p>Background</p> <p>Two problems complicate the study of selection in viral genomes: Firstly, the presence of genes in overlapping reading frames implies that selection in one reading frame can bias our estimates of neutral mutation rates in another reading frame. Secondly, the high mutation rates we are likely to encounter complicate the inference of a reliable alignment of genomes. To address these issues, we develop a model that explicitly models selection in overlapping reading frames. We then integrate this model into a statistical alignment framework, enabling us to estimate selection while explicitly dealing with the uncertainty of individual alignments. We show that in this way we obtain un-biased selection parameters for different genomic regions of interest, and can improve in accuracy compared to using a fixed alignment.</p> <p>Results</p> <p>We run a series of simulation studies to gauge how well we do in selection estimation, especially in comparison to the use of a fixed alignment. We show that the standard practice of using a ClustalW alignment can lead to considerable biases and that estimation accuracy increases substantially when explicitly integrating over the uncertainty in inferred alignments. We even manage to compete favourably for general evolutionary distances with an alignment produced by GenAl. We subsequently run our method on HIV2 and Hepatitis B sequences.</p> <p>Conclusion</p> <p>We propose that marginalizing over all alignments, as opposed to using a fixed one, should be considered in any parametric inference from divergent sequence data for which the alignments are not known with certainty. Moreover, we discover in HIV2 that double coding regions appear to be under less stringent selection than single coding ones. Additionally, there appears to be evidence for differential selection, where one overlapping reading frame is under positive and the other under negative selection.</p

Real-world evidence in health technology assessment of high-risk medical devices: fit for purpose?

Health technology assessment (HTA) of medical devices (MDs) increasingly rely on real-world evidence (RWE). The aim of this study was to evaluate the type and the quality of the evidence used to assess the (cost-)effectiveness of high risk MDs (Class III) by HTA agencies in Europe (four European HTA agencies and EUnetHTA), with particular focus on RWE. Data were extracted from HTA reports on the type of evidence demonstrating (cost-)effectiveness, and the quality of observational studies of comparative effectiveness using the Good Research for Comparative Effectiveness principles. 25 HTA reports were included that incorporated 28 observational studies of comparative effectiveness. Half of the studies (46%) took important confounding and/or effect modifying variables into account in the design and/or analyses. The most common way of including confounders and/or effect modifiers was through multivariable regression analysis. Other methods, such as propensity score matching, were rarely employed. Furthermore, meaningful analyses to test key assumptions were largely omitted. Resulting recommendations from HTA agencies on MDs is therefore (partially) based on evidence which is riddled with uncertainty. Considering the increasing importance of RWE it is important that the quality of observational studies of comparative effectiveness are systematically assessed when used in decision-making

Variation in use of targeted therapies for metastatic renal cell carcinoma

__Background:__ For patients with metastatic renal cell carcinoma (mRCC), targeted therapies have entered the market since 2006. The aims of this study were to evaluate the uptake and use of targeted therapies for mRCC in The Netherlands, examine factors associated with the prescription of targeted therapies in daily clinical practice and study their effectiveness in terms of overall survival (OS). __Methods:__ Two cohorts from PERCEPTION, a population-based registry of mRCC patients, were used: a 2008-2010 Cohort (n = 645) and a 2011-2013 Cohort (n = 233). Chi-squared tests for trend were used to study time trends in the use of targeted therapy. Patients were grouped based on the eligibility criteria of the SUTENT trial, the trial that led to sunitinib becoming standard of care, to investigate the use of targeted therapies amongst patients fulfilling those criteria. Multi-level logistic regression was used to identify patient subgroups that are less likely to receive targeted therapies. __Results:__ Approximately one-third of patients fulfilling SUTENT trial eligibility criteria did not receive any targeted therapy (29 % in the 2008-2010 Cohort; 35 % in the 2011-2013 Cohort). Patients aged 65+ years were less likely to receive targeted therapy in both cohorts and different risk groups (odds ratios range between 0.84-0.92); other factors like number of metastatic sites were of influence in some subgroups. Amongst treated patients, there was a decreasing trend in sunitinib use over time (p = 0.0061), and an increasing trend in pazopanib use (p = 0.0005). __Conclusions:__ Targeted therapies have largely replaced interferon-alfa as first-line standard of care. Nevertheless, many eligible patients in Dutch daily practice did not receive targeted therapies despite their ability to improve survival. Reasons for their apparent underutilisation should be examined more carefully

Health-related quality of life and its determinants in patients with metastatic renal cell carcinoma

__Purpose:__ Based on improvements of progression-free survival (PFS), new agents for metastatic renal cell carcinoma (mRCC) have been approved. It is assumed that one of the benefits is a delay in health-related quality of life (HRQoL) deterioration as a result of a delay in progression of disease. However, little data are available supporting this relationship. This study aims to provide insight into the most important determinants of HRQoL (including progression of disease) of patients with mRCC. __Methods:__ A patient registry (PERCEPTION) was created to evaluate treatment of patients with (m)RCC in the Netherlands. HRQoL was measured, using the EORTC QLQ-C30 and EQ-5D-5L, every 3 months in the first year of participation in the study, and every 6 months in the second year. Participation started as soon as possible following a diagnosis of (m)RCC. Random effects models were used to study associations between HRQoL and patient and disease characteristics, symptoms and treatment. __Results:__ Eighty-seven patients with mRCC completed 304 questionnaires. The average EORTC QLQ-C30 global health status was 69 (SD, 19) before progression and 61 (SD, 22) after progression of disease. Similarly, the average EQ-5D utility was 0.75 (SD, 0.19) before progression and 0.66 (SD, 0.30) after progression of disease. The presence of fatigue, pain, dyspnoea, and the application of radiotherapy were associated with significantly lower EQ-5D utilities. __Conclusions:__ Key drivers for reduced HRQoL in mRCC are disease symptoms. Since symptoms increase with progression of disease, targeted therapies that increase PFS are expected to postpone reductions in HRQoL in mRCC

Effectiveness of Seizure Dogs for People With Severe Refractory Epilepsy:Results From the EPISODE Study

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate whether people living with severe medically refractory epilepsy (PSRE) benefit from a seizure dog. METHODS: An individual-level stepped-wedge randomized controlled trial was conducted. The study was conducted in the Netherlands among adults with daily to weekly seizures. All participants were included simultaneously (on June 1, 2019) while receiving usual care. Then, during the 36-month follow-up, they received a seizure dog in a randomized sequence. Participants kept a seizure diary and completed 3-monthly surveys. Seizure frequency was the primary outcome. Secondary outcomes included seizure-free days, seizure severity, health-related quality of life (HRQoL), and well-being. Data were analyzed using generalized linear mixed modeling (GLMM). The models assumed a delayed intervention effect, starting when the seizure dog reached an advanced stage of training. Effects were calculated as changes per 28-day period with the intervention. RESULTS: Data were collected from 25 participants, of whom 20 crossed over to the intervention condition. The median follow-up was 19 months with usual care and 12 months with the intervention. On average, participants experienced 115 (SD 164) seizures per 28-day period in the usual care condition and 73 (SD 131) seizures in the intervention condition. Seven participants achieved a reduction of 50% or more at the end of follow-up. GLMM indicated a 3.1% decrease in seizure frequency for each consecutive 28-day period with the intervention (0.969, 95% CI 0.960-0.977). Furthermore, an increase in the number of seizure-free days was observed (1.012, 95% CI 1.009, 1.015), but no effect on seizure severity measured with the NHS3. Generic HRQoL scores improved, as reflected in the decrease in EQ-5D-5L utility decrement (0.975, 95% CI 0.954-0.997). Smaller improvements were observed on overall self-rated HRQoL, epilepsy-specific HRQoL, and well-being, measured with the EQ VAS, QOLIE-31-P, and ICECAP-A, respectively. DISCUSSION: Seizure dogs reduce seizure frequency, increase the number of seizure-free days, and improve the quality of life of PSRE. The magnitude of the effect on generic HRQoL indicates that seizure dogs benefit PSRE beyond the impact on seizure frequency alone. Early discontinuation of seizure dog partnerships suggests that this intervention is not suitable for all PSRE and requires further study. TRIAL REGISTRATION INFORMATION: This study was registered in the Dutch Trial Register (NL6682) on November 28, 2017. Participants were enrolled on June 1, 2019. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that seizure dogs are associated with a decrease in seizure frequency in adult patients with medically refractory epilepsy.</p

Do boys differ from girls in navigating through hypertext environments when learning?

Walhout, J., Brand-Gruwel, S., Van Dijk, M. L., Jarodzka, H., De Groot, R. H. M., Kester, L., & Kirschner, P. A. (2012, November). Do boys differ from girls in navigating through hypertext environments? Paper presented at the ICO Fall School 2012, Girona, Spain.Since hypertext learning environments (HLE) are widely used in education, it is important to study the effects and consequences of its use. Earlier research suggests that the outcomes of learning based on hypertext environments, depends on learner characteristics in conjunction hypertext specific features. Since the variety in interfaces is enormous, students are challenged to develop new methods of wayfinding for each HLE. It is therefore important to develop interfaces that facilitate learning as much as possible. In this paper a user characteristic (sex) and a hypertext feature (navigational support) are studied. Preliminary results show that there is no difference in sex or navigational support regarding task performance.Open Universiteit, Centre for Learning Sciences and Technologie

A cost of illness study of hypoglycaemic events in insulin-treated diabetes in the Netherlands

__Objectives__ Patients with diabetes mellitus are at a risk for hypoglycaemia. Besides the burden of hypoglycaemia for patients, hypoglycaemia poses an economic burden to society. The aim of th