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Enabling precision medicine by unravelling disease pathophysiology: quantifying signal transduction pathway activity across cell and tissue types.

ABSTRACT: Signal transduction pathways are important in physiology and pathophysiology. Targeted drugs aim at modifying pathogenic pathway activity, e.g., in cancer. Optimal treatment choice requires assays to measure pathway activity in individual patient tissue or cell samples. We developed a method enabling quantitative measurement of functional pathway activity based on Bayesian computational model inference of pathway activity from measurements of mRNA levels of target genes of the pathway-associated transcription factor. Oestrogen receptor, Wnt, and PI3K-FOXO pathway assays have been described previously. Here, we report model development for androgen receptor, Hedgehog, TGF?, and NF?B pathway assays, biological validation on multiple cell types, and analysis of data from published clinical studies (multiple sclerosis, amyotrophic lateral sclerosis, contact dermatitis, Ewing sarcoma, lymphoma, medulloblastoma, ependymoma, skin and prostate cancer). Multiple pathway analysis of clinical prostate cancer (PCa) studies showed increased AR activity in hyperplasia and primary PCa but variable AR activity in castrate resistant (CR) PCa, loss of TGF? activity in PCa, increased Wnt activity in TMPRSS2:ERG fusion protein-positive PCa, active PI3K pathway in advanced PCa, and active PI3K and NF?B as potential hormonal resistance pathways. Potential value for future clinical practice includes disease subtyping and prediction and targeted therapy response prediction and monitoring.

SUBMITTER: van de Stolpe A

PROVIDER: S-EPMC6367506 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Enabling precision medicine by unravelling disease pathophysiology: quantifying signal transduction pathway activity across cell and tissue types.

van de Stolpe Anja A Holtzer Laurent L van Ooijen Henk H Inda Marcia Alves de MA Verhaegh Wim W

Scientific reports 20190207 1

Signal transduction pathways are important in physiology and pathophysiology. Targeted drugs aim at modifying pathogenic pathway activity, e.g., in cancer. Optimal treatment choice requires assays to measure pathway activity in individual patient tissue or cell samples. We developed a method enabling quantitative measurement of functional pathway activity based on Bayesian computational model inference of pathway activity from measurements of mRNA levels of target genes of the pathway-associated ...[more]

PMID: 30733525

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Project description:BackgroundExamples of precision medicine are complex interventions featuring both testing and treatment components. Because of this complexity, there are often barriers to the introduction of such interventions. Few economic evaluations attempt to determine the impact of these barriers on the cost-effectiveness of the intervention. This study presents a case study economic evaluation that illustrates how the value of implementation methods may be used to quantify the impact of capacity constraints in a decision-analytic model.MethodsA baseline decision-analytic model-based economic evaluation of ALK mutation testing was reproduced from a published technology appraisal. Three constraints (commissioning awareness, localization of testing, and pathology laboratory capacity) were identified using qualitative interviews, parameterized, and incorporated into the model. Value of implementation methods were used alongside incremental cost-effectiveness ratios (ICERs) to quantify the impact on the cost-effectiveness and net monetary benefit (NMB) of each capacity constraint and from the 3 constraints combined.ResultsEach of the 3 capacity constraints resulted in a loss of NMB ranging from £7773 (0.1% of the total) per year for localized testing to £4,907,893 (77%) for a lack of awareness about commissioning ALK testing. When combined, the constraints resulted in a loss of NMB of £5,289,414 (83%). The localization and limited pathology capacity constraints slightly increased the ICER, but the lack of commissioning awareness constraint did not change the ICER.ConclusionsCapacity constraints may have a significant impact on the NMB produced by examples of precision medicine. Value of implementation methods can be used to quantify the impact of such constraints by combining the impact of the constraints on the cost-effectiveness of the intervention with the impact on the number of patients receiving the intervention.HighlightsWhile capacity constraints may prevent the use of precision medicine in clinical practice, economic evaluations rarely account for the impact of such barriers.This study demonstrates how constraints can be identified using qualitative methods and subsequently incorporated into decision-analytic models using quantitative value of implementation methods.In addition, this article demonstrates how value of implementation methods can be used to account for the impact of capacity constraints on the costs and benefits of an intervention as well as the number of patients receiving the intervention.In the case study presented herein, a capacity constraint reducing patient access to an example of precision medicine caused the biggest loss of net monetary benefit.Health economists should consider moving beyond incremental cost-effectiveness ratios to measures of total net monetary benefit to fully capture the impact of implementing precision medicine.

Dataset Information

Enabling precision medicine by unravelling disease pathophysiology: quantifying signal transduction pathway activity across cell and tissue types.

Publications

Enabling precision medicine by unravelling disease pathophysiology: quantifying signal transduction pathway activity across cell and tissue types.

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