Transparency in health economic modeling : options, issues and potential solutions

Economic models are increasingly being used by health economists to assess the value of health technologies and inform healthcare decision making. However, most published economic models represent a kind of black box, with known inputs and outputs but undisclosed internal calculations and assumptions. This lack of transparency makes the evaluation of the model results challenging, complicates comparisons between models, and limits the reproducibility of the models. Here, we aim to provide an overview of the possible steps that could be undertaken to make economic models more transparent and encourage model developers to share more detailed calculations and assumptions with their peers. Scenarios with different levels of transparency (i.e., how much information is disclosed) and reach of transparency (i.e., who has access to the disclosed information) are discussed, and five key concerns (copyrights, model misuse, confidential data, software, and time/resources) pertaining to model transparency are presented, along with possible solutions. While a shift toward open-source models is underway in health economics, as has happened before in other research fields, the challenges ahead should not be underestimated. Importantly, there is a pressing need to find an acceptable trade-off between the added value of model transparency and the time and resources needed to achieve such transparency. To this end, it will be crucial to set incentives at different stakeholder levels. Despite the many challenges, the many benefits of publicly sharing economic models make increased transparency a goal worth pursuing

Differential regulation of iron chelator-induced IL-8 synthesis via MAP kinase and NF-κB in immortalized and malignant oral keratinocytes

Abstract Background Interleukin-8 (IL-8) is a cytokine that plays an important role in tumor progression in a variety of cancer types; however, its regulation is not well understood in oral cancer cells. In the present study, we examined the expression and mechanism of IL-8 in which it is involved by treating immortalized (IHOK) and malignant human oral keratinocytes (HN12) cells with deferoxamine (DFO). Methods IL-8 production was measured by an enzyme-linked immunoabsorbent assay and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Electrophoretic mobility shift assays was used to determine NF-κB binding activity. Phosphorylation and degradation of the I-κB were analyized by Western blot. Results IHOK cells incubated with DFO showed increased expression of IL-8 mRNA, as well as higher release of the IL-8 protein. The up-regulation of DFO-induced IL-8 expression was higher in IHOK cells than in HN12 cells and was concentration-dependent. DFO acted additively with IL-1β to strongly up-regulate IL-8 in IHOK cells but not in HN12 cells. Accordingly, selective p38 and ERK1/2 inhibitors for both kinases abolished DFO-induced IL-8 expression in both IHOK and HN12 cells. Furthermore, DFO induced the degradation and phosphorylation of IκB, and activation of NF-κB. The IL-8 inducing effects of DFO were mediated by a nitric oxide donor (S-nitrosoglutathione), and by pyrrolidine dithiocarbamate, an inhibitor of NF-κB, as well as by wortmannin, which inhibits the phosphatidylinositol 3-kinase-dependent activation of NAD(P)H oxidase. Conclusion This results demonstrate that DFO-induced IL-8 acts via multiple signaling pathways in immortalized and malignant oral keratinocytes, and that the control of IL-8 may be an important target for immunotheraphy against human oral premalignant lesions.</p

Modelling the impact of atherosclerosis on drug release and distribution from coronary stents

Although drug-eluting stents (DES) are now widely used for the treatment of coronary heart disease, there remains considerable scope for the development of enhanced designs which address some of the limitations of existing devices. The drug release profile is a key element governing the overall performance of DES. The use of in vitro, in vivo, ex vivo, in silico and mathematical models has enhanced understanding of the factors which govern drug uptake and distribution from DES. Such work has identified the physical phenomena determining the transport of drug from the stent and through tissue, and has highlighted the importance of stent coatings and drug physical properties to this process. However, there is limited information regarding the precise role that the atherosclerotic lesion has in determining the uptake and distribution of drug. In this review, we start by discussing the various models that have been used in this research area, highlighting the different types of information they can provide. We then go on to describe more recent methods that incorporate the impact of atherosclerotic lesions

Topographic Spread of Inferior Colliculus Activation in Response to Acoustic and Intracochlear Electric Stimulation

The design of contemporary multichannel cochlear implants is predicated on the presumption that they activate multiple independent sectors of the auditory nerve array. The independence of these channels, however, is limited by the spread of activation from each intracochlear electrode across the auditory nerve array. In this study, we evaluated factors that influence intracochlear spread of activation using two types of intracochlear electrodes: (1) a clinical-type device consisting of a linear series of ring contacts positioned along a silicon elastomer carrier, and (2) a pair of visually placed (VP) ball electrodes that could be positioned independently relative to particular intracochlear structures, e.g., the spiral ganglion. Activation spread was estimated by recording multineuronal evoked activity along the cochleotopic axis of the central nucleus of the inferior colliculus (ICC). This activity was recorded using silicon-based single-shank, 16-site recording probes, which were fixed within the ICC at a depth defined by responses to acoustic tones. After deafening, electric stimuli consisting of single biphasic electric pulses were presented with each electrode type in various stimulation configurations (monopolar, bipolar, tripolar) and/or various electrode orientations (radial, off-radial, longitudinal). The results indicate that monopolar (MP) stimulation with either electrode type produced widepread excitation across the ICC. Bipolar (BP) stimulation with banded pairs of electrodes oriented longitudinally produced activation that was somewhat less broad than MP stimulation, and tripolar (TP) stimulation produced activation that was more restricted than MP or BP stimulation. Bipolar stimulation with radially oriented pairs of VP ball electrodes produced the most restricted activation. The activity patterns evoked by radial VP balls were comparable to those produced by pure tones in normal-hearing animals. Variations in distance between radially oriented VP balls had little effect on activation spread, although increases in interelectrode spacing tended to reduce thresholds. Bipolar stimulation with longitudinally oriented VP electrodes produced broad activation that tended to broaden as the separation between electrodes increased.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41383/1/10162_2004_Article_4026.pd

UFSRAT:Ultra-fast shape recognition with atom types -The discovery of novel bioactive small molecular scaffolds for FKBP12 and 11βHSD1

MOTIVATION:Using molecular similarity to discover bioactive small molecules with novel chemical scaffolds can be computationally demanding. We describe Ultra-fast Shape Recognition with Atom Types (UFSRAT), an efficient algorithm that considers both the 3D distribution (shape) and electrostatics of atoms to score and retrieve molecules capable of making similar interactions to those of the supplied query. RESULTS:Computational optimization and pre-calculation of molecular descriptors enables a query molecule to be run against a database containing 3.8 million molecules and results returned in under 10 seconds on modest hardware. UFSRAT has been used in pipelines to identify bioactive molecules for two clinically relevant drug targets; FK506-Binding Protein 12 and 11β-hydroxysteroid dehydrogenase type 1. In the case of FK506-Binding Protein 12, UFSRAT was used as the first step in a structure-based virtual screening pipeline, yielding many actives, of which the most active shows a KD, app of 281 µM and contains a substructure present in the query compound. Success was also achieved running solely the UFSRAT technique to identify new actives for 11β-hydroxysteroid dehydrogenase type 1, for which the most active displays an IC50 of 67 nM in a cell based assay and contains a substructure radically different to the query. This demonstrates the valuable ability of the UFSRAT algorithm to perform scaffold hops. AVAILABILITY AND IMPLEMENTATION:A web-based implementation of the algorithm is freely available at http://opus.bch.ed.ac.uk/ufsrat/

A community approach to mortality prediction in sepsis via gene expression analysis.

Improved risk stratification and prognosis prediction in sepsis is a critical unmet need. Clinical severity scores and available assays such as blood lactate reflect global illness severity with suboptimal performance, and do not specifically reveal the underlying dysregulation of sepsis. Here, we present prognostic models for 30-day mortality generated independently by three scientific groups by using 12 discovery cohorts containing transcriptomic data collected from primarily community-onset sepsis patients. Predictive performance is validated in five cohorts of community-onset sepsis patients in which the models show summary AUROCs ranging from 0.765-0.89. Similar performance is observed in four cohorts of hospital-acquired sepsis. Combining the new gene-expression-based prognostic models with prior clinical severity scores leads to significant improvement in prediction of 30-day mortality as measured via AUROC and net reclassification improvement index These models provide an opportunity to develop molecular bedside tests that may improve risk stratification and mortality prediction in patients with sepsis.y NIGMS Glue Grant Legacy Award R24GM102656. J.F.B.-M., R.A., and E.T. were supported by Instituto de Salud Carlos III (grants EMER07/050, PI13/02110, PI16/01156). R.J.L. was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001417. The CAPSOD study was supported by NIH (U01AI066569, P20RR016480, HHSN266200400064C). P.K. is supported by grants from Bill Melinda Gates Foundation, R01 AI125197-01, 1U19AI109662, and U19AI057229, outside the submitted work. The GAinS study was supported by the National Institute for Health Research through the Comprehensive Clinical Research Network for patient recruitment; Wellcome Trust (Grants 074318 [to J.C.K.], and 090532/Z/09/Z [core facilities Wellcome Trust Centre for Human Genetics including High-Throughput Genomics Group]); European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013)/ERC Grant agreement no. 281824 (to J.C.K.), the Medical Research Council (98082 [to J.C.K.]); UK Intensive Care Society; and NIHR Oxford Biomedical Research Centre. The Duke HAI study was supported by a research agreement between Duke University and Novartis Vaccines and Diagnostics, Inc. According to the terms of the agreement, representatives of the sponsor had an opportunity to review and comment on a draft of the manuscript. The authors had full control of the analyses, the preparation of the manuscript, and the decision to submit the manuscript for publication. For the University of Florida ‘P50’ Study, data were obtained from the Sepsis and Critically Illness Research Center (SCIRC) at the University of Florida College of Medicine, which is supported in part by NIGMS P50 GM111152. This work was supported by Defense Advanced Research Projects Agency and the Army Research Office through Grant W911NF-15-1-0107.