title: Reducing confounding and suppression effects in TCGA data: an integrated analysis of chemotherapy response in ovarian cancer.
abstract: BACKGROUND
  Despite initial response in adjuvant chemotherapy, ovarian cancer patients treated with the combination of paclitaxel and carboplatin frequently suffer from recurrence after few cycles of treatment, and the underlying mechanisms causing the chemoresistance remain unclear. Recently, The Cancer Genome Atlas (TCGA) research network concluded an ovarian cancer study and released the dataset to the public. The TCGA dataset possesses large sample size, comprehensive molecular profiles, and clinical outcome information; however, because of the unknown molecular subtypes in ovarian cancer and the great diversity of adjuvant treatments TCGA patients went through, studying chemotherapeutic response using the TCGA data is difficult. Additionally, factors such as sample batches, patient ages, and tumor stages further confound or suppress the identification of relevant genes, and thus the biological functions and disease mechanisms.
  
  
  RESULTS
  To address these issues, herein we propose an analysis procedure designed to reduce suppression effect by focusing on a specific chemotherapeutic treatment, and to remove confounding effects such as batch effect, patient's age, and tumor stages. The proposed procedure starts with a batch effect adjustment, followed by a rigorous sample selection process. Then, the gene expression, copy number, and methylation profiles from the TCGA ovarian cancer dataset are analyzed using a semi-supervised clustering method combined with a novel scoring function. As a result, two molecular classifications, one with poor copy number profiles and one with poor methylation profiles, enriched with unfavorable scores are identified. Compared with the samples enriched with favorable scores, these two classifications exhibit poor progression-free survival (PFS) and might be associated with poor chemotherapy response specifically to the combination of paclitaxel and carboplatin. Significant genes and biological processes are detected subsequently using classical statistical approaches and enrichment analysis.
  
  
  CONCLUSIONS
  The proposed procedure for the reduction of confounding and suppression effects and the semi-supervised clustering method are essential steps to identify genes associated with the chemotherapeutic response.
authors.affiliation: Department of Electrical and Computer Engineering, Texas A&M University, College Station, TX, USA.
authors.forename: Fang-Han
authors.initials: FH
authors.lastname: Hsu
authors.forename: Erchin
authors.initials: E
authors.lastname: Serpedin
authors.forename: Tzu-Hung
authors.initials: TH
authors.lastname: Hsiao
authors.forename: Alexander J R
authors.initials: AJ
authors.lastname: Bishop
authors.forename: Edward R
authors.initials: ER
authors.lastname: Dougherty
authors.forename: Yidong
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D016190:Carboplatin / Q000627:therapeutic use; D016000:Cluster Analysis; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D016208:Databases, Factual; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D016190:Carboplatin; D017239:Paclitaxel