Adapting a Plant Tissue Model to Animal Development: Introducing Cell Sliding into VirtualLeaf.

Cell-based, mathematical modeling of collective cell behavior has become a prominent tool in developmental biology. Cell-based models represent individual cells as single particles or as sets of interconnected particles and predict the collective cell behavior that follows from a set of interaction rules. In particular, vertex-based models are a popular tool for studying the mechanics of confluent, epithelial cell layers. They represent the junctions between three (or sometimes more) cells in confluent tissues as point particles, connected using structural elements that represent the cell boundaries. A disadvantage of these models is that cell-cell interfaces are represented as straight lines. This is a suitable simplification for epithelial tissues, where the interfaces are typically under tension, but this simplification may not be appropriate for mesenchymal tissues or tissues that are under compression, such that the cell-cell boundaries can buckle. In this paper, we introduce a variant of VMs in which this and two other limitations of VMs have been resolved. The new model can also be seen as on off-the-lattice generalization of the Cellular Potts Model. It is an extension of the open-source package VirtualLeaf, which was initially developed to simulate plant tissue morphogenesis where cells do not move relative to one another. The present extension of VirtualLeaf introduces a new rule for cell-cell shear or sliding, from which cell rearrangement (T1) and cell extrusion (T2) transitions emerge naturally, allowing the application of VirtualLeaf to problems of animal development. We show that the updated VirtualLeaf yields different results than the traditional vertex-based models for differential adhesion-driven cell sorting and for the neighborhood topology of soft cellular networks.

Methods for Communicating the Impact of Parameter Uncertainty in a Multiple-Strategies Cost-Effectiveness Comparison.

PURPOSE: Analyzing and communicating uncertainty is essential in medical decision making. To judge whether risks are acceptable, policy makers require information on the expected outcomes but also on the uncertainty and potential losses related to the chosen strategy. We aimed to compare methods used to represent the impact of uncertainty in decision problems involving many strategies, enhance existing methods, and provide an open-source and easy-to-use tool. METHODS: We conducted a systematic literature search to identify methods used to represent the impact of uncertainty in cost-effectiveness analyses comparing multiple strategies. We applied the identified methods to probabilistic sensitivity analysis outputs of 3 published decision-analytic models comparing multiple strategies. Subsequently, we compared the following characteristics: type of information conveyed, use of a fixed or flexible willingness-to-pay threshold, output interpretability, and the graphical discriminatory ability. We further proposed adjustments and integration of methods to overcome identified limitations of existing methods. RESULTS: The literature search resulted in the selection of 9 methods. The 3 methods with the most favorable characteristics to compare many strategies were 1) the cost-effectiveness acceptability curve (CEAC) and cost-effectiveness acceptability frontier (CEAF), 2) the expected loss curve (ELC), and 3) the incremental benefit curve (IBC). The information required to assess confidence in a decision often includes the average loss and the probability of cost-effectiveness associated with each strategy. Therefore, we proposed the integration of information presented in an ELC and CEAC into a single heat map. CONCLUSIONS: This article presents an overview of methods presenting uncertainty in multiple-strategy cost-effectiveness analyses, with their strengths and shortcomings. We proposed a heat map as an alternative method that integrates all relevant information required for health policy and medical decision making. HIGHLIGHTS: To assess confidence in a chosen course of action, decision makers require information on both the probability and the consequences of making a wrong decision.This article contains an overview of methods for presenting uncertainty in multiple-strategy cost-effectiveness analyses.We propose a heat map that combines the probability of cost-effectiveness from the cost-effectiveness acceptability curve (CEAC) with the consequences of a wrong decision from the expected loss curve.Collapsing of the CEAC can be reduced by relaxing the CEAC, as proposed in this article.Code in Microsoft Excel and R is provided to easily analyze data using the methods discussed in this article.

Cost-Effectiveness of Parallel Versus Sequential Testing of Genetic Aberrations for Stage IV Non-Small-Cell Lung Cancer in the Netherlands.

PURPOSE: A large number of targeted treatment options for stage IV nonsquamous non-small-cell lung cancer with specific genetic aberrations in tumor DNA is available. It is therefore important to optimize diagnostic testing strategies, such that patients receive adequate personalized treatment that improves survival and quality of life. The aim of this study is to assess the efficacy (including diagnostic costs, turnaround time (TAT), unsuccessful tests, percentages of correct findings, therapeutic costs, and therapeutic effectiveness) of parallel next generation sequencing (NGS)-based versus sequential single-gene-based testing strategies routinely used in patients with metastasized non-small-cell lung cancer in the Netherlands. METHODS: A diagnostic microsimulation model was developed to simulate 100,000 patients with prevalence of genetic aberrations, extracted from real-world data from the Dutch Pathology Registry. These simulated patients were modeled to undergo different testing strategies composed of multiple tests with different test characteristics including single-gene and panel tests, test accuracy, the probability of an unsuccessful test, and TAT. Diagnostic outcomes were linked to a previously developed treatment model, to predict average long-term survival, quality-adjusted life-years (QALYs), costs, and cost-effectiveness of parallel versus sequential testing. RESULTS: NGS-based parallel testing for all actionable genetic aberrations is on average €266 cheaper than single-gene-based sequential testing, and detects additional relevant targetable genetic aberrations in 20.5% of the cases, given a TAT of maximally 2 weeks. Therapeutic costs increased by €8,358, and 0.12 QALYs were gained, leading to an incremental cost-effectiveness ratio of €69,614/QALY for parallel versus sequential testing. CONCLUSION: NGS-based parallel testing is diagnostically superior over single-gene-based sequential testing, as it is cheaper and more effective than sequential testing. Parallel testing remains cost-effective with an incremental cost-effectiveness ratio of 69,614 €/QALY upon inclusion of therapeutic costs and long-term outcomes.

Cost-Effectiveness of Surveillance Scanning Strategies after Curative Treatment of Non-Small-Cell Lung Cancer.

BACKGROUND: After curative treatment of primary non-small-cell lung cancer (NSCLC), patients undergo intensive surveillance with the aim to detect recurrences from the primary tumor or metachronous second primary lung cancer as early as possible and improve overall survival. However, the benefit of surveillance is debated. Available evidence is of low quality and conflicting. Microsimulation modeling facilitates the exploration of the impact of different surveillance strategies and provides insight into the cost-effectiveness of surveillance. METHODS: A microsimulation model was used to simulate a range of computed tomography (CT)-based surveillance schedules, differing in the frequency and duration of CT surveillance. The impact on survival, quality-adjusted life-years, costs, and cost-effectiveness of each schedule was assessed. RESULTS: Ten of 108 strategies formed the cost-effectiveness frontier; that is, these were the strategies with the optimal cost-health benefit balance. Per person, the discounted QALYs of these strategies varied between 5.72 and 5.81 y, and discounted costs varied between €9892 and €19,259. Below a willingness-to-pay threshold of €50,000/QALY, no scanning is the preferred option. For a willingness-to-pay threshold of €80,000/QALY, surveillance scanning every 2 y starting 1 y after curative treatment becomes the best option, with €11,860 discounted costs and 5.76 discounted QALYs per person. The European Society for Medical Oncology guideline strategy was more expensive and less effective than several other strategies. CONCLUSION: Model simulations suggest that limited CT surveillance scanning after the treatment of primary NSCLC is cost-effective, but the incremental health-benefit remains marginal. However, model simulations do suggest that the guideline strategy is not cost-effective.

Prediction of Microscopic Metastases in Patients with Metachronous Oligo-Metastases after Curative Treatment of Non-Small Cell Lung Cancer: A Microsimulation Study.

Metachronous oligo-metastatic disease is variably defined as one to five metastases detected after a disease-free interval and treatment of the primary tumour with curative intent. Oligo-metastases in non-small cell lung cancer (NSCLC) are often treated with curative intent. However additional metastases are often detected later in time, and the 5-year survival is low. Burdensome surgical treatment in patients with undetected metastases may be avoided if patients with a high versus low risk of undetected metastases can be separated. Because there is no clinical data on undetected metastases available, a microsimulation model of the development and detection of metastases in 100,000 hypothetical stage I NSCLC patients with a controlled primary tumour was constructed. The model uses data from the literature as well as patient-level data. Calibration was used for the unobservable model parameters. Metastases can be detected by a scheduled scan, or an unplanned scan when the patient develops symptoms. The observable information at time of detection is used to identify subgroups of patients with a different risk of undetectable metastases. We identified the size and number of detected oligo-metastases, as well as the presence of symptoms that are the most important risk predictors. Based on these predictors, patients could be divided into a low-risk and a high-risk group, having a model-based predicted probability of 8.1% and 89.3% to have undetected metastases, respectively. Currently, the model is based on a synthesis of the literature data and individual patient-level data that were not collected for the purpose of this study. Optimization and validation of the model is necessary to allow clinical usability. We describe the type of data that needs to be collected to update our model, as well as the design of such a validation study.

Cost-effectiveness of stereotactic body radiation therapy versus video assisted thoracic surgery in medically operable stage I non-small cell lung cancer: A modeling study.

OBJECTIVES: Stage I non-small cell lung cancer (NSCLC) can be treated with either Stereotactic Body Radiotherapy (SBRT) or Video Assisted Thoracic Surgery (VATS) resection. To support decision making, not only the impact on survival needs to be taken into account, but also on quality of life, costs and cost-effectiveness. Therefore, we performed a cost-effectiveness analysis comparing SBRT to VATS resection with respect to quality adjusted life years (QALY) lived and costs in operable stage I NSCLC. MATERIALS AND METHODS: Patient level and aggregate data from eight Dutch databases were used to estimate costs, health utilities, recurrence free and overall survival. Propensity score matching was used to minimize selection bias in these studies. A microsimulation model predicting lifetime outcomes after treatment in stage I NSCLC patients was used for the cost-effectiveness analysis. Model outcomes for the two treatments were overall survival, QALYs, and total costs. We used a Dutch health care perspective with 1.5 % discounting for health effects, and 4 % discounting for costs, using 2018 cost data. The impact of model parameter uncertainty was assessed with deterministic and probabilistic sensitivity analyses. RESULTS: Patients receiving either VATS resection or SBRT were estimated to live 5.81 and 5.86 discounted QALYs, respectively. Average discounted lifetime costs in the VATS group were €29,269 versus €21,175 for SBRT. Difference in 90-day excess mortality between SBRT and VATS resection was the main driver for the difference in QALYs. SBRT was dominant in at least 74 % of the probabilistic simulations. CONCLUSION: Using a microsimulation model to combine available evidence on survival, costs, and health utilities in a cost-effectiveness analysis for stage I NSCLC led to the conclusion that SBRT dominates VATS resection in the majority of simulations.

Patient-reported Outcomes After the Treatment of Early Stage Non-small-cell Lung Cancer With Stereotactic Body Radiotherapy Compared With Surgery.

INTRODUCTION: As there is increasing evidence for comparable survival after either stereotactic body radiotherapy (SBRT) or surgery for patients with stage I non-small-cell lung cancer (NSCLC), treatment impact on the quality of life (QoL) is essential for well-informed decision-making. Our previous work evaluated health utility between surgery and SBRT in stage I NSCLC. The aim of this secondary analysis is to directly compare QoL in the first year after SBRT and surgery. MATERIALS AND METHODS: QoL was assessed at baseline and 3, 6, and 12 months after treatment. Two prospectively collected databases of patients with clinically proven stage I NSCLC, from 2 large hospitals in the Netherlands, were pooled (n = 306; 265 patients were treated with SBRT and 41 patients with surgery). To correct for confounding, propensity scores were calculated, to be selected for surgical treatment. A mixed model analysis was used to study differences in QoL between the 2 treatments. RESULTS: The 41 surgical patients were matched to 41 SBRT patients on propensity score with a 1:1 ratio. At baseline, patients in the surgery group report a lower QoL compared with patients in the SBRT group. However, during the first year after treatment, no clinical meaningful differences were observed, except for role functioning, between patients treated using either modality. CONCLUSION: This study comparing a matched cohort revealed no clinically significant differences in QoL following either SBRT or surgery for early stage NSCLC. These results support the hypothesis that surgery and SBRT are comparable treatments.

Differences in Longitudinal Health Utility between Stereotactic Body Radiation Therapy and Surgery in Stage I Non-Small Cell Lung Cancer.

INTRODUCTION: There is an ongoing debate on the optimal treatment for stage I NSCLC, with increasing evidence for comparable health outcomes after surgery and stereotactic body radiation therapy (SBRT). For clinical decision making, the experienced quality of life, summarized as health utility, is of importance to choosing between treatments. In this study, we evaluated differences in longitudinal health utility in stage I NSCLC in the first year after surgical resection versus after SBRT before any recurrence of disease. We also assessed the impact of potential prognostic variables on health utility. METHODS: Prospectively collected databases containing data on patients with stage I NSCLC treated with either SBRT or surgery were pooled from two large hospitals in the Netherlands. Quality of life data were measured by the Quality of Life Questionnaire-Core 30 questionnaire at baseline and 3, 6, and 12 months after treatment. Health utility (measured using the European Quality of Life Five-Dimension questionnaire) was calculated from the Quality of Life Questionnaire-Core 30 questionnaire by using a mapping algorithm. Propensity score matching was used to adjust for selection bias. Treatment effects were estimated for the matched patients by using a longitudinal mixed model approach. RESULTS: After correction for Eastern Cooperative Oncology Group score, sex, and age, the difference in 1-year averaged health utility between the SBRT and surgery groups was 0.026 (95% confidence interval: 0.028-0.080). Differences in health utility decreased over time. CONCLUSIONS: A small but not statistically significant difference in health utility was found between patients with stage I NSCLC treated with surgery and those treated with SBRT. Current analysis strengthens existing evidence that SBRT is an equivalent treatment option for early-stage NSCLC. Comparative cost-effectiveness remains to be determined.