Application of genome-wide expression analysis to human health and disease.
The application of genome-wide expression analysis to a large-scale, multicentered program in critically ill patients poses a number of theoretical and technical challenges. We describe here an analytical and organizational approach to a systematic evaluation of the variance associated with genome-wide expression analysis specifically tailored to study human disease. We analyzed sources of variance in genome-wide expression analyses performed with commercial oligonucleotide arrays. In addition, variance in gene expression in human blood leukocytes caused by repeated sampling in the same subject, among different healthy subjects, among different leukocyte subpopulations, and the effect of traumatic injury, were also explored. We report that analytical variance caused by sample processing was acceptably small. Blood leukocyte gene expression in the same individual over a 24-h period was remarkably constant. In contrast, genome-wide expression varied significantly among different subjects and leukocyte subpopulations. Expectedly, traumatic injury induced dramatic changes in apparent gene expression that were greater in magnitude than the analytical noise and interindividual variance. We demonstrate that the development of a nation-wide program for gene expression analysis with careful attention to analytical details can reduce the variance in the clinical setting to a level where patterns of gene expression are informative among different healthy human subjects, and can be studied with confidence in human disease.
Cobb
J Perren
JP
Department of Surgery, Washington University, St. Louis, MO 63130, USA.
Mindrinos
Michael N
MN
Miller-Graziano
Carol
C
Calvano
Steve E
SE
Baker
Henry V
HV
Xiao
Wenzhong
W
Laudanski
Krzysztof
K
Brownstein
Bernard H
BH
Elson
Constance M
CM
Hayden
Douglas L
DL
Herndon
David N
DN
Lowry
Stephen F
SF
Maier
Ronald V
RV
Schoenfeld
David A
DA
Moldawer
Lyle L
LL
Davis
Ronald W
RW
Tompkins
Ronald G
RG
Baker
Henry V
HV
Bankey
Paul
P
Billiar
Timothy
T
Brownstein
Bernard H
BH
Calvano
Steve E
SE
Camp
David
D
Chaudry
Irshad
I
Cobb
J Perren
JP
Davis
Ronald W
RW
Elson
Constance M
CM
Freeman
Bradley
B
Gamelli
Richard
R
Gibran
Nicole
N
Harbrecht
Brian
B
Hayden
Douglas L
DL
Heagy
Wyrta
W
Heimbach
David
D
Herndon
David N
DN
Horton
Jureta
J
Hunt
John
J
Laudanski
Krzysztof
K
Lederer
James
J
Lowry
Stephen F
SF
Maier
Ronald V
RV
Mannick
John
J
McKinley
Bruce
B
Miller-Graziano
Carol
C
Mindrinos
Michael N
MN
Minei
Joseph
J
Moldawer
Lyle L
LL
Moore
Ernest
E
Moore
Frederick
F
Munford
Robert
R
Nathens
Avery
A
O'keefe
Grant
G
Purdue
Gary
G
Rahme
Laurence
L
Remick
Daniel
D
Sailors
Matthew
M
Schoenfeld
David A
DA
Shapiro
Michael
M
Silver
Geoffrey
G
Smith
Richard
R
Stephanopoulos
Gregory
G
Stormo
Gary
G
Tompkins
Ronald G
RG
Toner
Mehmet
M
Warren
Shaw
S
West
Michael
M
Wolfe
Steven
S
Xiao
Wenzhong
W
Young
Vernon
V
D016000:Cluster Analysis; D015870:Gene Expression; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D015337:Multicenter Studies as Topic / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods* / Q000592:standards; D018579:Patient Selection; D025341:Principal Component Analysis; D015203:Reproducibility of Results; D013048:Specimen Handling / Q000379:methods; D014947:Wounds and Injuries / Q000378:metabolism