Enabling More Sophisticated Analysis of Gene Expression Profiles for Understanding Diseases and Optimizing Treatments

Participants: Abha Belorkar, Difeng Dong, Donny Soh, Jingjing Jin, Chuan Hock Koh, Kevin Lim, Limsoon Wong

Background

We survey the progress in the analysis of gene expression profiling data for the purposes of disease subtype diagnosis, new subtype discovery, and understanding of diseases and treatment responses. We find existing works fall short on several issues: these works provide little information on the interplay between selected genes and proteins; the collection of pathways that can be used, evaluated, and ranked against the observed expression data is limited; and a comprehensive set of rules for reasoning about relevant molecular events has not been compiled and formalized.

Objectives

We thus envision an advanced integrated framework, and are developing a system based on it, to provide biologically inspired solutions. It comprises:

Automated analysis and extraction of information from biomedical texts;
Targeted construction of known pathways; and
Direct hypothesis generation based on logical reasoning on, and tests for, consistencies and inconsistencies of observed data against known pathways.

Selected Publications

Gene expression analysis based on pathways

Donny Soh, Difeng Dong, Yike Guo, Limsoon Wong. Enabling More Sophisticated Gene Expression Analysis for Understanding Diseases and Optimizing Treatments. ACM SIGKDD Explorations, 9(1):3--14, June 2007. PDF
Limsoon Wong. Using Biological Networks in Protein Function Prediction and Gene Expression Analysis. Internet Mathematics, 7(4):274--298, December 2011. PDF.
Difeng Dong, Chun-Ying Cui, Benjamin Mow, Limsoon Wong. Deciphering Drug Action and Escape Pathways: An Example on Nasopharyngeal Carcinoma. Proceedings of 1st International Conference on Bioinformatics and Computational Biology (BICOB2009), pages 199--210, New Orleans, USA, 8-10 April 2009. PDF, Drug Pathway Decipherer V1.0 (Nov 2007), Drug Pathway Decipherer V2.0 (Dec 2008)
Donny Soh, Difeng Dong, Yike Guo, Limsoon Wong. Consistency, Comprehensiveness, and Compatibility of Pathway Databases. BMC Bioinformatics, 11:449, September 2010. PDF, Supplementary Data, PathwayAPI Online.
Donny Soh, Difeng Dong, Yike Guo, Limsoon Wong. Finding Consistent Disease Subnetworks Across Microarray Datasets. BMC Genomics, 12(Suppl. 13):S15, November 2011. PDF, Supplementary Data
Kevin Lim, Limsoon Wong. Finding consistent disease subnetworks using PFSNet. Bioinformatics, 30(2):189--196, January 2014. PDF, PFSNet v1.0, PFSNet v2.0
Kevin Lim, Zhenhua Li, Kwok Pui Choi, Limsoon Wong. A quantum leap in the reproducibility, precision, and sensitivity of gene expression profile analysis even when sample size is extremely small. Journal of Bioinformatics and Computational Biology, 13(4):1550018, August 2015. PDF, ESSNet v1.3
Daniel Boon Loong Teh, Ankshita Prasad, Wenxuan Jiang, Mohd Zacky Ariffin, Sanjay Khanna, Abha Belorkar, Limsoon Wong, Xiaogang Liu, Angelo H. All. Transcriptome analysis reveals neuroprotective aspects of human reactive astrocytes induced by interleekin 1beta. Scientific Reports, 7:13988, October 2017. PDF
Abha Belorkar, Rajanikanth Vadigepalli, Limsoon Wong. SPSNet: Subpopulation-sensitive network-based analysis of heterogeneous gene expression data. BMC Systems Biology, 12(Suppl 2):28, March 2018. PDF, SPSNet v1.0

Gene expression normalization
Chuan Hock Koh, Limsoon Wong. Embracing noise to improve cross-batch prediction accuracy. BMC Systems Biology, 6(Suppl 2):S3, December 2012. PDF
Abha Belorkar, Limsoon Wong. GFS: Fuzzy preprocessing for effective gene expression analysis. BMC Bioinformatics, 17(Suppl 17):540, December 2016. PDF
Wilson Wen Bin Goh, Judy Chia-Ghee Sng, Jie Yin Yee, Yuen Mei See, Tih-Shih Lee, Limsoon Wong, Jimmy Lee. Can peripheral blood-derived gene expression characterize individuals at ultra-high risk for psychosis? Computational Psychiatry, 1:168--183, December 2017 PDF

Gene expression analysis based on model checking
Chuan Hock Koh, Masao Nagasaki, Ayumu Saito, Limsoon Wong, Satoru Miyano. DA 1.0: Parameter Estimation of Biological Pathways Using Data Assimilation Approach. Bioinformatics, 26(14):1794--1796, July 2010. PDF. DA 1.0 Software.
Chuan Hock Koh, Masao Nagasaki, Ayumu Saito, Chen Li, Limsoon Wong, Satoru Miyano. MIRACH: Efficient Model Checker for Quantitative Biological Pathway Models. Bioinformatics, 27(5):734-735, March 2011. PDF. MIRACH Software
C. Li, M. Nagasaki, C. H. Koh, S. Miyano. Online Model Checking Approach based Parameter Estimation to a Neuronal Fate Decision Simulation Model in C. elegans with HFPNe. Molecular Biosystems, 7(5):1576--1592, 2011.
Chuan Hock Koh, Sucheendra K. Palaniappan, P. S. Thiagarajan, Limsoon Wong. Improved statistical model checking methods for pathways analysis. BMC Bioinformatics, 13(Suppl 17):S15, December 2012. PDF

Gene expression analysis based on other models
Wen-Son Hsieh, Ross Soo, Bee-Keow Peh, Thomas Loh, Difeng Dong, Donny Soh, Limsoon Wong, Simon Green, Judy Chiao, Chun-Ying Cui, Yoke-Fong Lai, Soo-Chin Lee, Benjamin Mow, Richie Soong, Manuel Salto-Tellez, Boon-Cher Goh. Pharmacodynamic Effects of Seliciclib, an Orally Administered Cell Cycle Modulator, in Undifferentiated Nasopharyngeal Cancer. Clinical Cancer Research, 15(4):1435--1442, February 2009. PDF
Thomas Thamboo, Richie Soong, Limsoon Wong, Baidah Ahmad, Yaw-Chyn Lim, Ming Teh. Determination of a molecular signature of acute T-cell-mediated renal allograft rejection using quantitative real-time RT-PCR of 45 genes on a low density array. Pathology, 43(1):72--75, January 2011.
Wen Lee Tan, Bhaskar Bhattacharya, Marie Chiew Hsia Loh, Indirikumar Balasubramanian, Mohamed Akram, Difeng Dong, Limsoon Wong, Bhavin Thakkar, Manuel Salto-Tellez, Ross Soo, Iduna Fichtner, Barry Iacopetta, Richie Soong. Low cytosine triphosphate synthase 2 expression renders resistance to 5-fluorouracil in colorectal cancer. Cancer Biology & Therapy, 11(6):599--608, March 2011.
Renhua Song, Qian Liu, Gyorgy Hutvagner, Hung Nguyen, Kotagiri Ramamohanarao, Limsoon Wong, Jinyan Li. Rule discovery and distance separation to detect reliable miRNA biomarkers for the diagnosis of lung squamous cell carcinoma. BMC Genomics, 15(Suppl 9):S16, December 2014. PDF
Allen Eng Juh Yeoh, Zhenhua Li, Difeng Dong, Yi Lu, Jan Trka, Shirley Kow Yin Kham, Ah Moy Tan, Hany Ariffin, Limsoon Wong. Effective response metric (ERM-D8) using time-series gene expression profiling at diagnosis and day 8 of remission-induction therapy is a novel early prognostic marker to predict relapse in childhood acute lymphoblastic leukamia (ALL)---a Malaysia-Singapore ALL study. Blood, 124(21):2393, December 2014. PDF
Allen E.-J. Yeoh, Zhenhua Li, Difeng Dong, Yi Lu, Nan Jiang, Jan Trka, An Moy Tan, Hai Peng Lin, Thuan Chong Quah, Hany Ariffin, Limsoon Wong. Effective Response Metric: A novel tool to predict relapse in childhood acute lymphoblastic leukaemia using time-series gene expression profiling. British Journal of Haematology, 181(5):653--663, June 2018.

Dissertations

Donny Soh. Understanding Pathways. PhD thesis, Department of Computing, Imperial College London, UK, 2009.
Difeng Dong. Relapse Prediction in Childhood Acute Lymphoblastic Leukemia by Time-Series Gene Expression Profiling. PhD thesis, School of Computing, National University of Singapore, 2011.
Chuan Hock Koh. Embracing Noise in Bioinformatics. PhD thesis, NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, 2012.
Kevin Lim. Using biological networks and gene-expression profiles for the analysis of diseases. PhD thesis, School of Computing, National Uinversity of Singapore, 2015.
Abha Belorkar. Gene expression analysis in the presence of heterogeneity. PhD thesis, School of Computing, National Uinversity of Singapore, 2018.
ZHONG Xiaohu. Enabling More Sophisticated Analysis of Gene Expression Data. UROP Final Report, School of Computing, National University of Singapore, 2008.
NGUYEN Duc Phong. Analysis of the role of cis elements in the spatial regulation of Arabidopsis salt stress reponse. UROP Final Report, School of Computing, National University of Singapore, 2010.
CHAI Haoqiang. A Software Developed to Identify Gene Pairs with Violated Correlation in Disease Phenotype. UROP Final Report, Faculty of Science, National University of Singapore, 2010.
CHAI Haoqiang. Towards More Consistent and Reproducible Gene Expression Analysis. Honours Year Project Report, Faculty of Science, National University of Singapore, 2011.
CAO Yiqun. Evaluating the false positive rates of gene expression profile analysis approaches. UROP Final Report, Faculty of Science, National University of Singapore, 2014.

Selected Presentations

Limsoon Wong. Two Applications of Text Mining in Bioinformatics: Enhancing Protein Function Prediction and Enhancing Drug Pathway Inference. Invited talk at 7th Korea-Singapore Workshop on Bioinformatics & NLP, Seoul, Korea, 15 February 2008. PPT
Difeng Dong, Guimei Liu, Limsoon Wong. Drug Pathway Decipherer and Some Exciting Results in Protein Complex Prediction. Invited talk at Symposium on Biomolecular Mechanism Discovery with Computational Biology, Biopolis, Singapore, 14 August 2008. PPT
Limsoon Wong. Challenges in Understanding Pathways, Predicting Complexes, & Inferring Protein Function. Invited keynote at First International Workshop on Neuroinformatics, Bioinformatics, and Cognitive Science, South China University of Technology, Guangzhou, China, 4-6 June 2009. PPT
Limsoon Wong. Some of My Headaches in Gene Expression Analysis. Invited talk at Dept of Pediatrics, NUH, Singapore, 14 October 2009.
Limsoon Wong. Consistency and Comprehensiveness of Pathway Databases. Invited talk at 9th Korea-Singapore Workshop on Bioinformatics and NLP, KAIST, Daejeon, Korea, 23 February 2010. PPT
Limsoon Wong. Finding Consistent Disease Subnetworks. Invited talk at HKUST, Hong Kong, 26 March 2010. PPT
Limsoon Wong. Enabling Reproducible Gene Expression Analysis. International Outstanding Scientist Series, Key Laboratory of Systems Biology, SIBS, CAS, Shanghai, China, 26 February 2011.
Limsoon Wong. Enabling Reproducible Gene Expression Analysis Using Biological Pathways. Invited talk at 2nd IPM-NUS Workshop on Computational Biology, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran, 6 April 2011.
Limsoon Wong. Enabling Reproducible Gene Expression Analysis. Invited talk at 5th Moscow Conference on Computational Molecular Biology (MCCMB), Moscow State University, Moscow, Russia, 24 July 2011. PPT
Limsoon Wong. Delivering Reproducible Gene Expression Analysis. Invited lecture for Microarray Workshop on Gene Expression Analysis for Aspiring Clinician Researchers, Clinical Research Centre, NUS, 23 September 2011. PPT
Limsoon Wong. A Novel Principle for Childhood ALL Relapse Prediction. Invited talk at 10th Korea-Singapore Workshop on Bioinformatics and NLP (KSW), Daegeon, South Korea, 12 December 2011. PPT
Limsoon Wong. A Novel Principle for Childhood ALL Relapse Prediction. Invited talk at UTS AAI Bioinformatics Workshop 2012, University of Technology Sydney, NSW, Australia, 12 January 2012. PPT
Limsoon Wong. Analysis of Gene Expression and Proteomic Profiles based on Biological Networks. Tutorial at 10th Asia Pacific Bioinformatics Conference (APBC2012), Melbourne, Australia, 17-19 January 2012. PPT, Written notes
Limsoon Wong. Using Biological Networks for Protein Function Prediction, Biomarker Identification, and Other Problems in Computational Biology. Invited master class at 2012 International Winter School in Methods in Bioinformatics (WSMBio 2012), Tarragona, Spain, 20-24 February 2012. PPT
Limsoon Wong. Living with Noise. Invited talk at SinFra 2012, UPMC, Paris, 15 October 2012. PPT
Limsoon Wong. A Novel Principle for Childhood ALL Relapse Prediction. Invited talk at Inaugural Post-BDC2012 Personalized Medicine Workshop, Hunter Medical Research Institute, University of Newcastle, Australia, 7 December 2012.
Limsoon Wong. A Novel Principle for Childhood ALL Relapse Prediction. Talk at NUS-POLITEHNICA Workshop, University Politechnica Bucharest, Bucharest, Romania, 28 February 2013.
Limsoon Wong. A Novel Principle for Childhood ALL Relapse Prediction. Invited talk at University of Tehran, Tehran, Iran, 25 February 2013.
Limsoon Wong. Mining Testable Hypothesis from Big Data. Invited panel at SNU Bioinformatics Workshop and Biofestival 2013, Seoul National University, Seoul, Korea, 24 May 2013. PDF
Limsoon Wong. The use of context in gene expression and proteomic profile analysis. Invited talk at NUS-ENS Workshop on Novel Genome-Wide Approaches to Decipher Transcriptional and Epigenetic Regulation in Mammalian Cells, Ecole Normale Superior, Paris, France, 30 May 2013.
Limsoon Wong. The Use of Context in Gene Expression and Proteomic Profile Analysis. Invited master class at 2013 International Summer School on Trends in Computing (SSTiC2013), Tarragona, Spain, 22-26 July 2013. PPT
Limsoon Wong. Enabling more reproducible gene expression analysis. Invited talk at 13th Annual International Workshop on Bioinformatics and Systems Biology (IBSB2013), Kyoto, Japan, 1 August 2013. PPT
Limsoon Wong. Disease gene expression and proteomic profile analysis based on regulatory networks and systems. Invited master class at EMS Autumn School on Computational Aspects of Gene Regulation, Bedlewo, Poland, 13-19 October 2013. PDF
Limsoon Wong. The use of context in gene expression analysis. Invited talk at the 2013 Symposium on Complex Biodynamics & Networks, Institute for Advanced Biosciences - Keio University, Tsuruoka, Japan, 12 November 2013.
Limsoon Wong. How logic empowers statistics in the analysis of extremely high-dimensional data with extremely small sample sizes. Invited talk ar 4th Singapore Conference on Statistical Science, National University of Singapore, 7 February 2014.
Limsoon Wong. Computational thinking in genome and proteome analysis. Invited talk at International Conference on Next Generation Genomic View on Plants, Animals, and Microbes, National University of Singapore, 5 March 2014. PPT
Limsoon Wong. Finding consistent disease subnetworks in data with extremely small sample size. Invited talk at Qatar Biomedical Research Institute, Doha, 30 March 2014. PPT
Limsoon Wong. Big data in bioinformatics: Is more better?. Invited talk at KAUST CBRC Inauguration Symposium, Thuwal, Saudi Arabia, 8 June 2014. PPT
Limsoon Wong. Analysis of gene expression data of extremely small sample size. Invited talk at Guangxi University, Nanning, China, 22 September 2014. PPT
Limsoon Wong. A quantum leap in the reproducibility, precision, and sensitivity of gene-expression-profile analysis even when sample size is extremely small. Invited keynote at the 25th International Conference on Genome Informatics (GIW/ISCB-Asia), Tokyo, Japan, 15-17 December 2014. PPT
Limsoon Wong. A quantum leap in the reproducibility, precision, and sensitivity of gene-expression-profile analysis even when sample size is extremely small. Invited talk at the 4th IPM-NUS Workshop on Computational Biology, Tehran, Iran, 10 March 2015. PPT
Limsoon Wong. A novel principle for childhood ALL relapse prediction. Invited talk at 9th Asian Biophysics Association Symposium (ABA2015), Shangyu, China, 9-12 May 2015.
Limsoon Wong. Robust gene expression and proteomics profile analysis in the presence of undeclared heterogeneity. Invited talk at IPM Workshop on Systems Biology, Institute for Research in Fundamental Sciences, Tehran, Iran, 2 - 3 August 2017. PPT
Limsoon Wong. Anna Karenina and the careless null hypothesis in omics data analysis. Invited talk at IPM Workshop on Systems Biology, Institute for Research in Fundamental Sciences, Tehran, Iran, 2 - 3 August 2017. PPT

Acknowledgements

This project is supported in part by NUS ARF grant R-252-050-238-101/133 (Wong: 11/05 - 11/08), NUS URC grant R-252-000-274-112 (Wong: 10/06 - 09/09, Dong: 12/08 - 09/09), SERC PSF grant 072 101 0016 (Wong: 8/07 - 7/10, Soh: 1/09 - 12/09), NRF CRP grant NRF-G-CRP-2997-04-082(d) (Wong: 4/08 - 3/13, Dong: 10/09 - 12/10), MOE Tier-2 grant MOE2009-T2-2-004 (Wong, Goh, Jin: 4/10 - 3/13), an NUS NGS scholarship (Koh: 09/08 - 08/12), and an A*STAR AIP scholarship (Soh: 12/04 - 12/08).

Last updated: 12/6/2018, Limsoon Wong.