Data driven linear algebraic methods for analysis of molecular pathways

Application to disease progression in shock/trauma

Mary F. McGuire, M. Sriram Iyengar, David W Mercer

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Motivation: Although trauma is the leading cause of death for those below 45. years of age, there is a dearth of information about the temporal behavior of the underlying biological mechanisms in those who survive the initial trauma only to later suffer from syndromes such as multiple organ failure. Levels of serum cytokines potentially affect the clinical outcomes of trauma; understanding how cytokine levels modulate intra-cellular signaling pathways can yield insights into molecular mechanisms of disease progression and help to identify targeted therapies. However, developing such analyses is challenging since it necessitates the integration and interpretation of large amounts of heterogeneous, quantitative and qualitative data. Here we present the Pathway Semantics Algorithm (PSA), an algebraic process of node and edge analyses of evoked biological pathways over time for in silico discovery of biomedical hypotheses, using data from a prospective controlled clinical study of the role of cytokines in multiple organ failure (MOF) at a major US trauma center. A matrix algebra approach was used in both the PSA node and PSA edge analyses with different matrix configurations and computations based on the biomedical questions to be examined. In the edge analysis, a percentage measure of crosstalk called XTALK was also developed to assess cross-pathway interference. Results: In the node/molecular analysis of the first 24. h from trauma, PSA uncovered seven molecules evoked computationally that differentiated outcomes of MOF or non-MOF (NMOF), of which three molecules had not been previously associated with any shock/trauma syndrome. In the edge/molecular interaction analysis, PSA examined four categories of functional molecular interaction relationships - activation, expression, inhibition, and transcription - and found that the interaction patterns and crosstalk changed over time and outcome. The PSA edge analysis suggests that a diagnosis, prognosis or therapy based on molecular interaction mechanisms may be most effective within a certain time period and for a specific functional relationship.

Original languageEnglish (US)
Pages (from-to)372-387
Number of pages16
JournalJournal of Biomedical Informatics
Volume45
Issue number2
DOIs
StatePublished - Apr 1 2012

Fingerprint

Semantics
Disease Progression
Shock
Multiple Organ Failure
Molecular interactions
Wounds and Injuries
Cytokines
Crosstalk
Cell signaling
Molecules
Trauma Centers
Transcription
Computer Simulation
Cause of Death
Chemical activation
Therapeutics
Serum

Keywords

  • Biomedical informatics
  • Hypothesis generation
  • Signaling pathways
  • Systems biology
  • Trauma

ASJC Scopus subject areas

  • Computer Science Applications
  • Health Informatics

Cite this

Data driven linear algebraic methods for analysis of molecular pathways : Application to disease progression in shock/trauma. / McGuire, Mary F.; Sriram Iyengar, M.; Mercer, David W.

In: Journal of Biomedical Informatics, Vol. 45, No. 2, 01.04.2012, p. 372-387.

Research output: Contribution to journalArticle

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