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Transcript
Structure Learning for Inferring a Biological Pathway Charles Vaske Stuart Lab Biological Pathways • Cell is a dynamical system • Somewhat modularized (into pathways) • Given pathway elements, how do they communicate? – Protein modification – Gene expression changes Input • Set of genes essential to phenotype • RNAi perturbation - gene knockdown • Expression measurement S Genes - essential to phenotype - each is individually perturbed E Genes - affected by S Genes - expression is measured S genes & controls Input E Genes Desired Output: Structure Probabilistic Model • Binary Variable Domain • Restricted factor form – Deterministic signalling – Shared measurement error rates Markowetz, et al. 2005 Model Averaging • Maximum Likelihood estimate might not be interesting • Gain a posterior on particular model features First Attempt: All linear models • Calculate likelihood of data under each model • Find posterior of individual edges • Tiered Sgenes (matches initial discovery method) Link Robustness • Noise level estimated from replicate spots • Added noise to data, reran experiment 10 times QuickTime™ and a TIFF (U ncompressed) decompressor are needed to see this picture. Link Significance Link DEAD->GLUT GLUT->TFDP RLP32->KER TFDP->RLP32 CD53->DEAD CCR9->CD53 CCR9->ADAM21 ADAM21->CD53 ADAM21->DEAD CD53->ADAM21 ADAM21->CCR9 CD53->CCR9 CCR9->DEAD KER->RLP32 Quantile 0.998 0.998 0.988 0.988 0.900 0.888 0.859 0.859 0.852 0.839 0.836 0.816 0.805 0.693 Probability 0.998 0.999 0.966 0.966 0.668 0.641 0.582 0.582 0.547 0.501 0.480 0.418 0.356 0.160 Link Significance Experimentally Link DEAD->GLUT verified GLUT->TFDP RLP32->KER TFDP->RLP32 CD53->DEAD CCR9->CD53 CCR9->ADAM21 ADAM21->CD53 ADAM21->DEAD CD53->ADAM21 ADAM21->CCR9 CD53->CCR9 CCR9->DEAD KER->RLP32 Quantile 0.998 0.998 0.988 0.988 0.900 0.888 0.859 0.859 0.852 0.839 0.836 0.816 0.805 0.693 Probability 0.998 0.999 0.966 0.966 0.668 0.641 0.582 0.582 0.547 0.501 0.480 0.418 0.356 0.160 Scaling to More Sgenes • All linear permutations is a hack • MCMC structure sampling?
