Supplementary material is available at Bioinformatics online.

Software for our approach is available for download at: http://www.bioconductor.org/packages/release/bioc/html/ASSIGN.html and https://github.com/wevanjohnson/ASSIGN.

BackgroundThe growth factor receptor network (GFRN) plays a significant role in driving key oncogenic processes. However, assessment of global GFRN activity is challenging due to complex crosstalk among GFRN components, or pathways, and the inability to study complex signaling networks in patient tumors. Here, pathway-specific genomic signatures were used to interrogate GFRN activity in breast tumors and the consequent phenotypic impact of GRFN activity patterns.MethodsNovel pathway signatures were generated in human primary mammary epithelial cells by overexpressing key genes from GFRN pathways (HER2, IGF1R, AKT1, EGFR, KRAS (G12V), RAF1, BAD). The pathway analysis toolkit Adaptive Signature Selection and InteGratioN (ASSIGN) was used to estimate pathway activity for GFRN components in 1119 breast tumors from The Cancer Genome Atlas (TCGA) and across 55 breast cancer cell lines from the Integrative Cancer Biology Program (ICBP43). These signatures were investigated for their relationship to pro- and anti-apoptotic protein expression and drug response in breast cancer cell lines.ResultsApplication of these signatures to breast tumor gene expression data identified two novel discrete phenotypes characterized by concordant, aberrant activation of either the HER2, IGF1R, and AKT pathways (“the survival phenotype”) or the EGFR, KRAS (G12V), RAF1, and BAD pathways (“the growth phenotype”). These phenotypes described a significant amount of the variability in the total expression data across breast cancer tumors and characterized distinctive patterns in apoptosis evasion and drug response. The growth phenotype expressed lower levels of BIM and higher levels of MCL-1 proteins. Further, the growth phenotype was more sensitive to common chemotherapies and targeted therapies directed at EGFR and MEK. Alternatively, the survival phenotype was more sensitive to drugs inhibiting HER2, PI3K, AKT, and mTOR, but more resistant to chemotherapies.ConclusionsGene expression profiling revealed a bifurcation pattern in GFRN activity represented by two discrete phenotypes. These phenotypes correlate to unique mechanisms of apoptosis and drug response and have the potential of pinpointing targetable aberration(s) for more effective breast cancer treatments.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0429-x) contains supplementary material, which is available to authorized users.

Background Understanding complexity in healthcare has the potential to reduce decision and treatment uncertainty. Therefore, identifying both patient and task complexity may offer better task allocation and design recommendation for next generation health information technology system design. Objective To identify the specific complexity-contributing factors in the infectious disease domain and the relationship with the complexity perceived by clinicians. Method We observed and audio recorded the clinical rounds of three infectious disease teams. Thirty cases were observed for a period of four consecutive days. Transcripts were coded based on the clinical complexity-contributing factors from the clinical complexity model. Ratings of complexity on day 1 for each case were collected. We then used statistical methods to identify complexity-contributing factors in relationship to perceived complexity of clinicians. Results A factor analysis (principal component extraction with varimax rotation) of specific items revealed three factors (eigenvalues>2.0) explaining 47% of total variance, namely task interaction and goals (10 items, 26%, Cronbach’s Alpha=0.87), urgency and acuity (6 items, 11%, Cronbach’s Alpha=0.67), and psychosocial behavior (4 items, 10%, Cronbach’s alpha=0.55). A linear regression analysis showed no statistically significant association between complexity perceived by the physicians and objective complexity, which was measured from coded transcript by three clinicians (Multiple R-squared=0.13, p=0.61). There were no physician effects on the rating of perceived complexity. Conclusion Task complexity contributes significantly to overall complexity in the infectious disease domain. The different complexity-contributing factors found in this study can guide health information technology system designers and researchers for intuitive design. Different types of decision support tools can help to reduce the specific complexity- contributing factors found in this study. Future studies aimed at understanding clinical domain-specific complexity-contributing factors can ultimately improve task allocation and design for intuitive clinical reasoning.