In silico design of clinical trials: A method coming of age

Clermont, Gilles; Bartels, John; Kumar, Rukmini; Constantine, Gregory; Vodovotz, Yoram; Chow, Carson C.

doi:10.1097/01.ccm.0000142394.28791.c3

Cited by 172 publications

(173 citation statements)

References 45 publications

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“…The model fits the overall trend in data, but not quantitatively precise. The model is extended in Clermont et al (2004) to include living bacteria. A conundrum in the paper was the need of a very slow antiinflammatory mediator which the authors suggest to be cortisol Chow et al (2005).…”

Section: Modeling Backgroundmentioning

confidence: 99%

Integrated Inflammatory Stress (ITIS) Model

et al. 2017

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Integrated Inflammatory Stress (ITIS) ModelBangsgaard, Elisabeth O.; Hjorth, Poul G.; Olufsen, Mette S.; Mehlsen, Jesper; Ottesen, Johnny T. Published in: Bulletin of Mathematical BiologyLink to article, DOI: 10.1007/s11538-017-0293-2 Publication date: 2017 Document VersionPublisher's PDF, also known as Version of record Abstract During the last decade, there has been an increasing interest in the coupling between the acute inflammatory response and the Hypothalamic-Pituitary-Adrenal (HPA) axis. The inflammatory response is activated acutely by pathogen-or damagerelated molecular patterns, whereas the HPA axis maintains a long-term level of the stress hormone cortisol which is also anti-inflammatory. A new integrated model of the interaction between these two subsystems of the inflammatory system is proposed and coined the integrated inflammatory stress (ITIS) model. The coupling mechanisms describing the interactions between the subsystems in the ITIS model are formulated based on biological reasoning and its ability to describe clinical data. The ITIS model is calibrated and validated by simulating various scenarios related to endotoxin (LPS) exposure. The model is capable of reproducing human data of tumor necrosis factor alpha, adrenocorticotropic hormone (ACTH) and cortisol and suggests that repeated LPS injections lead to a deficient response. The ITIS model predicts that the most extensive response to an LPS injection in ACTH and cortisol concentrations is observed in the early hours of the day. A constant activation results in elevated levels of the variables in the model while a prolonged change of the oscillations in ACTH and

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Section: Modeling Backgroundmentioning

confidence: 99%

Integrated Inflammatory Stress (ITIS) Model

et al. 2017

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“…In silico trials are being explored to provide a virtual arena through which clinical trials of novel anti-cancer therapies can be tested (43). In such trials, a virtual patient would be given a virtual treatment and the outcomes of treatment can be measured (44). Although the intention is not to completely replace actual clinical trials involving real patients, in silico trials have the potential to reduce the number of patients required to perform a clinical trial as well as limiting the exposure of patients to adverse effects of trial medications (45).…”

Section: Future Directionsmentioning

confidence: 99%

Integration of advances in social media and mHealth technology are pivotal to successful cancer prevention and control

O’Leary

Zaheer

Redmond

et al. 2016

mHealth

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“…In silico (simulated) clinical trials are an inexpensive and increasingly popular means of gleaning translational knowledge from computational models [55][56][57][58][59]. Accordingly, these methods were utilized to test both current and hypothetical or cutting-edge therapies for inflammation in the setting of post-SCI PU.…”

Section: In Silico Clinical Trials For Post-sci Pressure Ulcersmentioning

confidence: 99%

A computational, tissue-realistic model of pressure ulcer formation in individuals with spinal cord injury

Ziraldo

Solovyev

Allegretti

et al. 2013

Journal of Critical Care

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People with spinal cord injury (SCI) are predisposed to pressure ulcers (PU). PU remain a significant burden in cost of care and quality of life despite improved mechanistic understanding and advanced interventions. An agent-based model (ABM) of ischemia/reperfusion-induced inflammation and PU (the PUABM) was created, calibrated to serial images of post-SCI PU, and used to investigate potential treatments in silico. Tissue-level features of the PUABM recapitulated visual patterns of ulcer formation in individuals with SCI. These morphological features, along with simulated cell counts and mediator concentrations, suggested that the influence of inflammatory dynamics caused simulations to be committed to "better" vs. "worse" outcomes by 4 days of simulated time and prior to ulcer formation. Sensitivity analysis of model parameters suggested that increasing oxygen availability would reduce PU incidence. Using the PUABM, in silico trials of anti-inflammatory treatments such as corticosteroids and a neutralizing antibody targeted at Damage-Associated Molecular Pattern molecules (DAMPs) suggested that, at best, early application at a sufficiently high dose could attenuate local inflammation and reduce pressure-associated tissue damage, but could not reduce PU incidence. The PUABM thus shows promise as an adjunct for mechanistic understanding, diagnosis, and design of therapies in the setting of PU. Author SummaryA virtual pressure ulcer was created as a platform to test therapies and determine the mechanisms most correlated with unfavorable outcomes. A layer of tissue fed with oxygen and diffusible molecules via blood vessels could develop an ulcer if pressure was applied, by simulating constriction of blood vessels in a circular region. Simulated ulcers were visually similar to digital photographs of ulcers in individuals with spinal cord injury in their irregular shapes, jagged edges, and overall progression in time. Statistical analyses of simulation outputs revealed that inflammation was an important determinant of ulcer severity and overall tissue damage. However, simulated clinical trials revealed that blocking the negative effects of inflammation could not prevent ulceration, and in order to be beneficial at all for this specific type of ulcer, anti-inflammatory treatments must be applied during the earliest stages of ulcer formation-before many clinical signs of ulceration appear.

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In silico design of clinical trials: A method coming of age

Cited by 172 publications

References 45 publications

Integrated Inflammatory Stress (ITIS) Model

Integrated Inflammatory Stress (ITIS) Model

Integration of advances in social media and mHealth technology are pivotal to successful cancer prevention and control

A computational, tissue-realistic model of pressure ulcer formation in individuals with spinal cord injury

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