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Conquering the C urse of D imensionality in G ene E xpression C ancer D iagnosis: T ough P roblem, S imple M odels. Minca Mramor 1 , Gregor Leban 1 , Janez Demšar 1 and Blaž Zupan 1,2 1 Faculty of C omputer and I nformation S cience University of Ljubljana, Slovenia
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Conquering the Curse of Dimensionality in Gene Expression Cancer Diagnosis: Tough Problem, Simple Models Minca Mramor1, Gregor Leban1,Janez Demšar1 and Blaž Zupan1,2 1 Faculty of Computer and Information Science University of Ljubljana, Slovenia 2 Department of Molecular and Human Genetics Baylor College of Medicine, Houston, USA
Cancer • epidemiology • 2nd cause of death in the developed world • increasing number of patients • carcinogenesis • a multi factorial and heterogeneous disease • non-lethal injury to the DNA of one cell • a multi step process
Use of gene expression microarrays in cancer research • uncovering the genetic mechanisms (loss of cell cycle control) • identification of specific genes • classification of different tumor types Final Goals • insight into carcinogenesis • improvement and individualization of treatment, • development of targeted therapeutics • identification of biomarkers
SRBCT Example: 6567 genes, 83 patients, 4 classes Khan et al. (Nature Medicine, 2001) • Initial cuts (image analysis failed – 2308 genes left) • 10 dominant components obtained with PCA • 3750 feed-forward neural networks • Rank genes with the ANN models, select best 96 • Clear separation of classes using MDS
Open Questions & Goals • Can graphs with clear class separation be found directly from data? • Can they include only original attributes? • How many of them are needed for good class separation? • How are these attributes (genes) related to cancer? • How useful are prevailing feature selection methods?
Methods: VizRank • Visualization techniques • Visualization scoring and ranking • Projection search
Methods (VizRank) • Visualization techniques • Visualization scoring and ranking • Projection search score = 0.76 score = 0.98
A snapshot of Orange data mining suite, showing VizRank ranking of best visualizations and the corresponding best-ranked scatterplot for the leukemia data set
Results For all investigated data sets VizRank found visualizations with a small number of genes (2-6) with clear separation of diagnostic classes. LEUKEMIA PROSTATE DLBCL SRBCT
Results MIXED LINEAGE LEUKEMIA
Results Scores for top-ranked visualizations [Probability of correct classification for k-NN classifier in projection plane]
Results: biological relevance of the genes in the best visual projections Genes annotated as cancer or cancer related according to the atlas of genetics and cytogenetics in oncology and haematology. The best radviz visualization of the prostate tumor data set: all six genes are cancer related PROSTATE TUMOR
Results: biological relevance of the genes in the best visual projections MIXED - LINEAGE LEUKEMIA DNTT (terminal deoxynucleotidyl transferase) – a unique DNA polymerase expressed in the lymphoid precursors and their malignant counterparts and an important marker of lymphoblastic leukemias MME (membrane metalloendopeptidase) or common acute lymphocytic leukemia antigen (CALLA) - an important cell surface marker in the diagnosis of human acute lymphocytic leukemia (ALL)
Results: biological relevance of the genes and an explanation of the outliers • SMCL and COID class express high levels of neuroendocrine tumors genes (ISL1) • For SQ lung carcinomas diagnostic criteria include evidence of squamous differentiation (KRT5) • Histological diversity of adenocarcinoma (AD) class in the lung cancer data set: • 12 AD were extrapulmonary metastases • seven adenocarcinomas display histological evidence of squamous features LUNG CANCER
How many “good” projectionsare there? Only a few [among several millions of possible projections].
Gene ranking methods • Signal-to-noise (S2N) (Golub et al., Science 1999) – univariate gene scoring statistic derived from the standard parametric t-test S2N = (µ0 - µ1)/(σ0 + σ1) µ = mean σ = standard deviation • ReliefF (Kononenko, 1994) –attribute scoring function sensitive to feature interactions
Results: all data sets include a subset of about 100 highly discriminating genes Histogram for actual attribute values Histogram for permuted data A permutation test to verify if these high discriminatory genes were assigned high scores by chance For all data sets histograms of ReliefF scores are skewed to the right, with a group of 50 – 100 most discriminating genes in the right tail
Results: S2N and ReliefF yield different gene ranking Spearman correlation coefficient (from 0.24 for the DLBCL data set to 0.89 for the MLL data set) 20 best genes from the scatterplot visualizations for the leukemia data set A relatively poor performance of ReliefF, similar to S2N (too large context due to high number of attributes in the data sets?)
Conclusion • Cancer diagnostic classes can be clearly separated using the expression data of only a few genes • Visualizations can • find small sets of most relevant genes • uncover interesting gene interactions • point to outliers • Our “visual” models are • simple • understandable and • significantly less sophisticated classification model than prevailing techniques in current cancer gene expression analysis
Small round blue cell tumors, data by Khan et al. (2001) THANK YOU! Minca Mramor, Gregor Leban, Janez Demšar and Blaž Zupan