Assessment of network perturbation amplitudes by applying high-throughput data to causal biological networks.
BACKGROUND
High-throughput measurement technologies produce data sets that have the potential to elucidate the biological impact of disease, drug treatment, and environmental agents on humans. The scientific community faces an ongoing challenge in the analysis of these rich data sources to more accurately characterize biological processes that have been perturbed at the mechanistic level. Here, a new approach is built on previous methodologies in which high-throughput data was interpreted using prior biological knowledge of cause and effect relationships. These relationships are structured into network models that describe specific biological processes, such as inflammatory signaling or cell cycle progression. This enables quantitative assessment of network perturbation in response to a given stimulus.


RESULTS
Four complementary methods were devised to quantify treatment-induced activity changes in processes described by network models. In addition, companion statistics were developed to qualify significance and specificity of the results. This approach is called Network Perturbation Amplitude (NPA) scoring because the amplitudes of treatment-induced perturbations are computed for biological network models. The NPA methods were tested on two transcriptomic data sets: normal human bronchial epithelial (NHBE) cells treated with the pro-inflammatory signaling mediator TNFα, and HCT116 colon cancer cells treated with the CDK cell cycle inhibitor R547. Each data set was scored against network models representing different aspects of inflammatory signaling and cell cycle progression, and these scores were compared with independent measures of pathway activity in NHBE cells to verify the approach. The NPA scoring method successfully quantified the amplitude of TNFα-induced perturbation for each network model when compared against NF-κB nuclear localization and cell number. In addition, the degree and specificity to which CDK-inhibition affected cell cycle and inflammatory signaling were meaningfully determined.


CONCLUSIONS
The NPA scoring method leverages high-throughput measurements and a priori literature-derived knowledge in the form of network models to characterize the activity change for a broad collection of biological processes at high-resolution. Applications of this framework include comparative assessment of the biological impact caused by environmental factors, toxic substances, or drug treatments.
Philip Morris International R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, Neuchâtel, 2000, Switzerland.
Florian
F
Martin
Ty M
TM
Thomson
Alain
A
Sewer
David A
DA
Drubin
Carole
C
Mathis
Dirk
D
Weisensee
Dexter
D
Pratt
Julia
J
Hoeng
Manuel C
MC
Peitsch
D002453:Cell Cycle; D006801:Humans; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D049490:Systems Biology / Q000379:methods*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha