1. Predicting Gene Functions from Text Using a Cross-Species Approach Emilia Stoica and Marti Hearst School of Information University of California, Berkeley Research Supported by NSF DBI-0317510 and a gift from Genentech

2. Goal Annotate genes with functional information derived from journal articles.

3. Gene Ontology (GO) Gene Ontology (GO) controlled vocabulary for functional annotation ~ 17,600 terms (circa July 2004) Organized into 3 distinct acyclic graphs molecular functions biological processes cellular locations More general terms are “parents” of less general terms: development (GO:0007275) is the parent of embryonic development (GO:0001756)

4. Challenges GO tokens might not appear explicitly Example: PubMed 10692450 GO:0008285: negative regulation of cell proliferation Occurs as: inhibition of cell proliferation GO tokens might not occur contiguously Example: PubMed 10734056, GO:0007186 : G-protein coupled receptor protein signaling pathway Occurs as: Results indicate that CCR1-mediated responses are regulated …in the signaling pathway, by receptor phosphorylation at the level of receptor G/protein coupling … CCR1 binds MIP-1 alpha.

5. Challenges The simplest strategy (assigning GO codes to genes simply because the GO tokens occur near the gene) yields a large number of false positives. Issues: a)The text does not contain evidence to support the annotation, b)The text contains evidence for the annotation, but the curator knows the gene to be involved in a function that is more general or more specific than the GO code matched in text.

6. Challenges GO contains hints about what kinds of evidence are required for annotation, e.g.: The text should mention co-purification, co- immunoprecipitation experiments Requiring these evidence terms does not seem to improve algorithms.

7. Related Work Mainly in the context of BioCreative competition (2004) Chiang and Yu 2003, 2004: Find phrase patterns commonly used in sentences describing gene functions (e.g., “gene plays an important role in”, “gene is involved in”) Final assignments made with a Naïve Bayes classifier Ray and Craven 2004, 2005: Learn a statistical model for each GO code (which words are likely to co-occur in the paragraphs containing GO codes); Decide among candidates via a multinomial Naïve Bayes classifier Rice et al. 2004: Train an SVM for each GO code. Target genes assigned best-scoring GO code.

8. Related Work, cont. Couto et al. 2004 Determine if the “information content” of the matching GO terms is larger than for all the candidate GO terms. Verspoor et al. 2004 Expand GO tokens with words that frequently co-occur in a training set; use a categorizer that explores the structure of the Gene Ontology to find best hits. Ehler and Ruch 2004: Treat each document as a query to be categorized Create a score based on a combination of pattern matching and TF*IDF weighting Annotate gene with top-scoring GO codes.

9. Our Approach Two main contributions: Use cross-species information (CSM) Check for biological (in) consistencies (CSC)

10. Cross-Species Match Main Idea Use orthologous genes [Genes of different species that have evolved directly from a common ancestor.] Assumption: Since there is an overlap between the genomes of the two species, their orthologs may share some functions, and consequently some GO codes Idea: to predict GO codes for target genes in target species, use the GO codes assigned to their orthologous genes We use Mouse vs. Human genes

11. General procedure Analyze text at sentence level Eliminate stop words, punctuation characters and divide the text into tokens using space as delimiter Normalize and match different variations of gene names using the algorithm of Bhalotia et al.’03 For every sentence that contains the target gene: A GO code is matched if the sentence contains a percentage of GO tokens larger than a threshold (0.75 for CSM and 1 for CSC)

12. Cross Species Match Algorithm CSM(g, a): For a target gene g, search in article a for only the GO codes annotated to its ortholog If at least 75% of the GO code terms are found in a sentence containing the gene name, the code is matched. Note: we must eliminate annotations of orthologs marked with IEA and ISS codes to avoid circular references.

13. Cross-Species Correlation Main Idea Observation: Since GO codes indicate gene function, it is logical for some to often co-occur in annotations and for others to rarely do so. Assumption: If one GO code tends to occur in the orthologous genes’ annotations when another one does not, then assume the second is not a valid assignment for the target species Example: If text seems to contain evidence for rRNA transcription ( GO:0009303) nucleolus (GO:0005737) and extracellular (GO:0005576), then extracellular is suspicious. The algorithm identifies the “suspicious” cases.

14. Cross-Species Correlation Algorithm For every pair of GO codes in the orthologous genes database, compute a X 2 coefficient. N: the total number of GO codes O 11 : # of times the ortholog is annotated with both GO 1 and GO 2 O 12 : # of times the ortholog is annotated with GO 1 but not GO 2 O 21 : # of times the ortholog is annotated with GO 2 but not GO 1 O 12 : # of times the ortholog is not annotated with GO 1 or GO 2 X2X2

15. Cross-Species Correlation Algorithm M(g,a) = GO codes matched in article a for gene g O(g) = GO codes assigned to the ortholog of g o = size of O(g), p = percentage (0.2) For every potentially matching GO code GO 1 in M(g,a) For every GO code GO 2 in O(g) Count how often X 2 ( GO 1,GO 2 ) is significant If this count is < p*o then assume GO 1 is not valid. Else assign GO 1 to g

16. Information Flow

17. Evaluation using BioCreative Task 2.2: Annotate 138 human genes with GO codes using 99 full text articles; For each annotation, provide the passage of text that the annotation was based upon. Annotations from participants were manually judged by human curators A prediction was considered “perfect” if the text passage contained the gene name, and provided evidence for annotating the gene with the GO code

18. Results on BioCreative Our research was conducted after the competition had past, so our annotations could not be judged by the same curators Used the “perfect predictions” (unfair to our system; ignores relevant predictions we find that other systems do not) Our prediction is correct if it matches a perfect prediction (e.g., vhl is annotated with transcription (GO:0006350) in PubMed 12169961 “ vhl inhibits transcription elongation, mRNA stability and PKC activity ”)

19. BioCreative Results SystemPrecisionTP (Recall)F-measure CSM0.3616 (0.07)0.11 CSC0.1844 (0.19)0.18 CSM+CSC0.2451 (0.21)0.23 Ray and Craven0.2152 (0.22)0.22 Chiang and Yu0.3337 (0.16)0.21 Ehler and Ruch0.1278 (0.33)0.18 Couto et al.0.0958 (0.25)0.13 Verspoor et al.0.0619 (0.08)0.07 Rice et al.0.0416 (0.07)0.05

20. Results on Larger Dataset A much larger test set has been made publicly available by Chiang and Yu. EBI human test set 4,410 genes 13,626 GO code annotations MGI mouse test set 2,188 genes 6,338 GO code annotations Note that Chiang and Yu used the same data for both training and testing.

21. Results on EBI Human and MGI datasets EBI human: 4,410 genes and 5,714 abstracts MGI: 2,188 genes and 1,947 abstracts DatasetSystemPrecisionRecallF-measure EBICSM0.290.030.06 CSM+CSC0.160.090.12 Chiang and Yu0.320.060.11 MGICSM0.330.050.09 CSC+CSC 0.170.12 0.14 Chiang and Yu0.330.050.09

22. Conclusions and Future Work We propose an algorithm that annotates genes with GO codes using the information available from other species Experimental results on three datasets show that our algorithm consistently achieves higher F-measures than other solutions Future improvements to our algorithm: - combine or use a voting scheme between the predictions our system makes and the predictions of a machine learning system - investigate how effective are other genes with sequences similar to the target gene (but not orthologous to the gene) for predicting the GO codes

23. Thank you! http://biotext.berkeley.edu Research Supported by NSF DBI-0317510 and a gift from Genentech

24. Example The marked accumulation of lipid droplets in LNCaP cells...is accompanied by an increase in phospholipid synthesis. The increase in PAP-2 might be related to changes in lipid metabolism… Since PAP-2 plays a pivotal role in the control of signal transduction by lipid mediator mediators, the ability of androgens to stimulate this enzyme in prostatic cells may provide opportunity for cross-talk between signaling pathways involving lipid mediators and androgens.

25. CSC Algorithm M(g,a) = GO codes matched in article a for gene g O(g) = GO codes annotated to the ortholog of g o = size of O(g), p = percentage (0.2) CSC(g,a) ={}; for every GO 1 in M(g,a) count = 0; for every GO 2 in O(g) if((X 2 ( GO 1,GO 2 )>3.84) && ( GO 1 ne GO 2 )) count++; if(count > p*o) add GO 1 to CSC(g,a);