PMID- 18923431
OWN - NLM
STAT- MEDLINE
DCOM- 20090622
LR  - 20240312
IS  - 1476-5470 (Electronic)
IS  - 1466-4879 (Print)
IS  - 1466-4879 (Linking)
VI  - 10
IP  - 2
DP  - 2009 Mar
TI  - Integrated analysis of genetic and proteomic data identifies biomarkers 
      associated with adverse events following smallpox vaccination.
PG  - 112-9
LID - 10.1038/gene.2008.80 [doi]
AB  - Complex clinical outcomes, such as adverse reaction to vaccination, arise from 
      the concerted interactions among the myriad components of a biological system. 
      Therefore, comprehensive etiological models can be developed only through the 
      integrated study of multiple types of experimental data. In this study, we apply 
      this paradigm to high-dimensional genetic and proteomic data collected to 
      elucidate the mechanisms underlying the development of adverse events (AEs) in 
      patients after smallpox vaccination. As vaccination was successful in all of the 
      patients under study, the AE outcomes reported likely represent the result of 
      interactions among immune system components that result in excessive or prolonged 
      immune stimulation. In this study, we examined 1442 genetic variables (single 
      nucleotide polymorphisms) and 108 proteomic variables (serum cytokine 
      concentrations) to model AE risk. To accomplish this daunting analytical task, we 
      employed the Random Forests (RF) method to filter the most important attributes, 
      then we used the selected attributes to build a final decision tree model. This 
      strategy is well suited to integrated analysis, as relevant attributes may be 
      selected from categorical or continuous data. Importantly, RF is a natural 
      approach for studying the type of gene-gene, gene-protein and protein-protein 
      interactions we hypothesize to be involved in the development of clinical AEs. RF 
      importance scores for particular attributes take interactions into account, and 
      there may be interactions across data types. Combining information from previous 
      studies on AEs related to smallpox vaccination with the genetic and proteomic 
      attributes identified by RF, we built a comprehensive model of AE development 
      that includes the cytokines intercellular adhesion molecule-1 (ICAM-1 or CD54), 
      interleukin-10 (IL-10), and colony stimulating factor-3 (CSF-3 or G-CSF) and a 
      genetic polymorphism in the cytokine gene interleukin-4 (IL4). The biological 
      factors included in the model support our hypothesized mechanism for the 
      development of AEs involving prolonged stimulation of inflammatory pathways and 
      an imbalance of normal tissue damage repair pathways. This study shows the 
      utility of RF for such analytical tasks, while both enhancing and reinforcing our 
      working model of AE development after smallpox vaccination.
FAU - Reif, D M
AU  - Reif DM
AD  - National Center for Computational Toxicology, US Environmental Protection Agency, 
      Research Triangle Park, NC 27711, USA. reif.david@epa.gov
FAU - Motsinger-Reif, A A
AU  - Motsinger-Reif AA
FAU - McKinney, B A
AU  - McKinney BA
FAU - Rock, M T
AU  - Rock MT
FAU - Crowe, J E Jr
AU  - Crowe JE Jr
FAU - Moore, J H
AU  - Moore JH
LA  - eng
GR  - R21-AI-59365/AI/NIAID NIH HHS/United States
GR  - R01-AI-59694/AI/NIAID NIH HHS/United States
GR  - R01-GM-2758/GM/NIGMS NIH HHS/United States
GR  - R01 AI059694-05/AI/NIAID NIH HHS/United States
GR  - N01AI25462/AI/NIAID NIH HHS/United States
GR  - N01-AI-25462/AI/NIAID NIH HHS/United States
GR  - R21 AI059365/AI/NIAID NIH HHS/United States
GR  - R01 AI059694/AI/NIAID NIH HHS/United States
GR  - K25 AI064625/AI/NIAID NIH HHS/United States
GR  - K25-AI-064625/AI/NIAID NIH HHS/United States
PT  - Clinical Trial
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
DEP - 20081016
PL  - England
TA  - Genes Immun
JT  - Genes and immunity
JID - 100953417
RN  - 0 (Biomarkers)
RN  - 0 (Cytokines)
RN  - 0 (Smallpox Vaccine)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
SB  - IM
MH  - Biomarkers/blood
MH  - Cytokines/*blood/*genetics
MH  - Decision Making, Computer-Assisted
MH  - Female
MH  - Humans
MH  - Inflammation/blood/chemically induced/genetics
MH  - Intercellular Adhesion Molecule-1/*blood/*genetics
MH  - Male
MH  - *Models, Biological
MH  - *Polymorphism, Single Nucleotide
MH  - Proteomics/methods
MH  - Smallpox Vaccine/administration & dosage/*adverse effects
MH  - Vaccination
PMC - PMC2692715
MID - NIHMS107982
EDAT- 2008/10/17 09:00
MHDA- 2009/06/23 09:00
PMCR- 2010/03/01
CRDT- 2008/10/17 09:00
PHST- 2008/10/17 09:00 [pubmed]
PHST- 2009/06/23 09:00 [medline]
PHST- 2008/10/17 09:00 [entrez]
PHST- 2010/03/01 00:00 [pmc-release]
AID - gene200880 [pii]
AID - 10.1038/gene.2008.80 [doi]
PST - ppublish
SO  - Genes Immun. 2009 Mar;10(2):112-9. doi: 10.1038/gene.2008.80. Epub 2008 Oct 16.