Metabolomics technologies enable the identification of putative biomarkers for numerous diseases; however, the influence of confounding factors on metabolite levels poses a major challenge in moving forward with such metabolites for pre-clinical or clinical applications.
To address this challenge, we analyzed metabolomics data from a colorectal cancer (CRC) study, and used seemingly unrelated regression (SUR) to account for the effects of confounding factors including gender, BMI, age, alcohol use, and smoking.
A SUR model based on 113 serum metabolites quantified using targeted mass spectrometry, identified 20 metabolites that differentiated CRC patients (n = 36), patients with polyp (n = 39), and healthy subjects (n = 83). Models built using different groups of biologically related metabolites achieved improved differentiation and were significant for 26 out of 29 groups. Furthermore, the networks of correlated metabolites constructed for all groups of metabolites using the ParCorA algorithm, before or after application of the SUR model, showed significant alterations for CRC and polyp patients relative to healthy controls.
The results showed that demographic covariates, such as gender, BMI, BMI2, and smoking status, exhibit significant confounding effects on metabolite levels, which can be modeled effectively.
These results not only provide new insights into addressing the major issue of confounding effects in metabolomics analysis, but also shed light on issues related to establishing reliable biomarkers and the biological connections between them in a complex disease.
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The authors gratefully acknowledge the support of the Cancer Care Engineering (CCE) project, a joint effort between the Oncological Sciences Center (Purdue Center for Cancer Research, NCI P30CA023168) in the Purdue University Discovery Park and the Indiana University Melvin and Bren Simon Cancer Center (NCI P30CA082709). Support for the CCE project is gratefully acknowledged from the Walther Cancer Foundation, NIH (UL1RR025761), DOD (USAMRMC (CDMRP) W81XWH-008-1-0065, 9107003) and the Regenstrief Foundation. Additional financial support from NIH (R03CA211831 to N.G.), the Walther Cancer Foundation Bioinformatics grant, and the Cancer Center Support Grant P30CA015704-40) is also gratefully acknowledged.
Conflict of interest
The authors declare that they have no competing interests.
Recruitment of patients and blood collections was made with written informed consent as per the approved Institutional Review Board protocols from Purdue University and Indiana University School of Medicine.
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Chen, C., Nagana Gowda, G.A., Zhu, J. et al. Altered metabolite levels and correlations in patients with colorectal cancer and polyps detected using seemingly unrelated regression analysis. Metabolomics 13, 125 (2017). https://doi.org/10.1007/s11306-017-1265-0