University of Texas at Austin

Using Biomedical Literature Mining to Consolidate the Set of Known Human Protein-Protein Interactions Razvan C. Bunescu Raymond J. Mooney Machine Learning Group Department of Computer Sciences University of Texas at Austin {razvan, mooney}@cs.utexas.edu Arun K. Ramani Edward M. Marcotte Institute for Cellular and Molecular Biology and Center for Computational Biology and Bioinformatics University of Texas at Austin {arun, marcotte}@icmb.utexas.edu

Outline ,[object Object],[object Object],[object Object],[object Object],[object Object]

Introduction ,[object Object],[object Object],[object Object],[object Object],[object Object],In synchronized human osteosarcoma cells, cyclin D1 is induced in early G1 and becomes associated with p9Ckshs1 , a Cdk-binding subunit.

Motivation ,[object Object],[object Object],[object Object],Aim : Automatically identify pairs of interacting proteins with high accuracy.

Outline ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Accuracy Benchmarks – Shared Functional Annotations ,[object Object],[object Object],[object Object],[object Object]

Accuracy Benchmarks – Shared Known Physical Interactions ,[object Object],[object Object],[object Object]

Accuracy Benchmarks – LLR Scoring Scheme ,[object Object],[object Object],[object Object],P(D|I) and P(D|-I) are the probabilities of observing the data D conditioned on the proteins sharing ( I ) or not sharing ( -I ) benchmark associations. ,[object Object]

Framework for Interaction Extraction Interactions Database ,[object Object],[object Object],[object Object],[object Object],Medline abstract Protein Extraction Medline abstract (proteins tagged) Interaction Extraction

Framework for Interaction Extraction ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[Lafferty et al. 2001]

1) A CRF tagger for protein names ,[object Object],O O O O O O B E O O O O O In synchronized human osteosarcoma cells , cyclin D1 is induced in early G1 ,[object Object],[object Object],[object Object],[object Object]

1) A CRF tagger for protein names ,[object Object],[object Object],[object Object],[object Object],IN VBN JJ NN NNS , NN NNP VBZ VBN IN JJ In synchronized human osteosarcoma cells , cyclin D1 is induced in early words after words before current word POS before POS after current POS

1) A CRF tagger for protein names ,[object Object],[object Object],[object Object],[object Object],[object Object]

2.1) Interaction Extraction using Co-citation Analysis ,[object Object],[object Object],N – total number of abstracts (750K) n – abstracts citing the first protein m – abstracts citing the second protein k – abstracts citing both proteins

2.1) Interaction Extraction using Co-citation Analysis ,[object Object],[object Object],[object Object]

2.1) Co-citation Analysis with Bayesian Reranking ,[object Object],[object Object],[object Object],Re-ranked Interactions Medline abstract CRF tagger Medline abstract (proteins tagged) Co-citation Analysis Ranked Interactions Naïve Bayes scores

Integrating Extracted Data with Existing Databases Extracted : 6,580 interactions between 3,737 human proteins Total: 31,609 interactions between 7,748 human proteins.

2.1) Co-citation Analysis: Evaluation

2.2) Learning of Interaction Extractors ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

AImed ,[object Object],[object Object],In synchronized human osteosarcoma cells, cyclin D1 is induced in early G1 and becomes associated with p9Ckshs1 , a Cdk-binding subunit. Immunoprecipitation experiments with human osteosarcoma cells and Ewing’s sarcoma cells demonstrated that cyclin D1 is associated with both p34cdc2 and p33cdk2 , and that cyclin D1 immune complexes exhibit appreciable histone H1 kinase activity … cyclin D1 … becomes associated with p9Ckshs1 => Interaction cyclin D1 is associated with both p34cdc2 => Interaction cyclin D1 is associated with both p34cdc2 and p33cdk2 => Interaction

ELCS (Extraction using Longest Common Subsequences) ,[object Object],[object Object],[object Object],[object Object],[Bunescu et al., 2005]

ERK (Extraction using a Relation Kernel) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

ERK (Extraction using a Relation Kernel) ,[object Object],[object Object],[object Object],S 1  In synchronized human osteosarcoma cells, cyclin D1 is induced in early G1 and becomes associated with p9Ckshs1 , a Cdk-binding subunit. S 2  Experiments with human osteosarcoma cells and Ewing’s sarcoma cells demonstrated that cyclin D1 is associated with both p34cdc2 and p33cdk2 , and ,[object Object],[object Object],[object Object]

Evaluation: ERK vs ELCS vs Manual ,[object Object],[object Object]

Evaluation: ERK vs ELCS vs Manual

Future Work & Conclusions ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

For Further Information ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Protein Interaction Datasets – Normalization ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Protein Interaction Datasets – Normalization ,[object Object],11,282 (3,863) 206 (206) 11,488 (3,918) 03/31/04 Orthology (core) 71,124 (6,228) 373 (373) 71,497 (6,257) 03/31/04 Orthology (all) 6,054 (2,747) 3,028 (3,028) 12,013 (4,122) 04/12/04 HPRD 5,663 (4,762) 549 (549) 6,212 (5,412) 08/03/04 BIND 12,336 (807) 160 (160) 12,497 (6,257) 08/03/04 Reactome Unique Is (Ps) Self Is (Ps) Total Is (Ps) Version Dataset

Accuracy of manually curated interactions 3.7 Non-core orthology 1.1 Non-core orthology 3.7 HPRD 2.1 Core orthology 5.0 Core orthology 2.1 HPRD N/A N/A 2.9 BIND N/A N/A 3.8 Reactome LLR Database LLR Database Physical Interaction Benchmark Functional Annotation Benchmark

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