Integrative genomics with mediation analysis in a survival context.
DNA copy number aberrations (DCNA) and subsequent altered gene expression profiles may have a major impact on tumor initiation, on development, and eventually on recurrence and cancer-specific mortality. However, most methods employed in integrative genomic analysis of the two biological levels, DNA and RNA, do not consider survival time. In the present note, we propose the adoption of a survival analysis-based framework for the integrative analysis of DCNA and mRNA levels to reveal their implication on patient clinical outcome with the prerequisite that the effect of DCNA on survival is mediated by mRNA levels. The specific aim of the paper is to offer a feasible framework to test the DCNA-mRNA-survival pathway. We provide statistical inference algorithms for mediation based on asymptotic results. Furthermore, we illustrate the applicability of the method in an integrative genomic analysis setting by using a breast cancer data set consisting of 141 invasive breast tumors. In addition, we provide implementation in R.
Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden ; Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Szilárd
S
Nemes
Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Toshima Z
TZ
Parris
Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Anna
A
Danielsson
Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Zakaria
Z
Einbeigi
Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden ; Division of Clinical Cancer Epidemiology, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
Gunnar
G
Steineck
Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Junmei Miao
JM
Jonasson
Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Khalil
K
Helou
D000465:Algorithms; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D019295:Computational Biology; D004247:DNA / Q000737:chemistry; D056915:DNA Copy Number Variations; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics; D011336:Probability; D016016:Proportional Hazards Models; D012313:RNA / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D012984:Software; D016019:Survival Analysis
D012333:RNA, Messenger; D012313:RNA; D004247:DNA