Feature Selection Methods of Gene Expression Based on Machine Learning: A Review
Keywords:
Machine learning, Gene expression, Feature selectionAbstract
This article offers a thorough analysis of feature selection strategies that use machine learning to analyze gene expression data. In order to extract significant biological insights, the explosion of high-dimensional genomic data has required the invention and use of sophisticated analysis techniques. In this situation, feature selection is essential because it finds the most pertinent genes that have a major impact on the prediction ability of machine learning models. The paper examines a range of feature selection techniques, classifying them into filter, wrapper, and embedding approaches, each having special advantages and disadvantages. The importance of gene expression data in comprehending the molecular mechanisms underlying complicated diseases and biological processes. The difficulties presented by high-dimensional datasets are next explored, with a focus on feature selection as a means of enhancing model interpretability, lowering computational cost, and raising prediction accuracy. In order to shed light on the fundamental ideas and practical uses of well-known feature selection algorithms, the writers thoroughly examine a number of them, including Mutual Information, Relief, and Recursive Feature Elimination (RFE). Additionally, the study assesses these methods' performance critically across a range of datasets and experimental situations, emphasizing important factors like interpretability, scalability, and resilience. The paper also discusses new developments in feature selection, such as the incorporation of deep learning techniques, ensemble methods, and domain expertise. In order to fully realize the promise of gene expression data for biomedical research and clinical applications, the study ends with a discussion of the present issues and prospective future directions in the field. This discussion emphasizes the significance of creating reliable and understandable feature selection techniques. This thorough study will be an invaluable tool for practitioners, researchers, and bioinformaticians in the field of genomics as they navigate the challenging terrain of feature selection techniques in the context of machine learning-based gene expression analysis.
References
Abdulqader, D. M., Abdulazeez, A. M., & Zeebaree, D. Q. (2020). Machine Learning Supervised Algorithms of Gene Selection: A Review. 62(03).
Ahmed, M., Seraj, R., & Islam, S. M. S. (2020). The k-means Algorithm: A Comprehensive Survey and Performance Evaluation. Electronics, 9(8), 1295. https://doi.org/10.3390/electronics9081295
Ahmed, O., & Brifcani, A. (2019). Gene Expression Classification Based on Deep Learning. 2019 4th Scientific International Conference Najaf (SICN), 145–149. https://doi.org/10.1109/SICN47020.2019.9019357
Al-Azzam, N., & Shatnawi, I. (2021). Comparing supervised and semi-supervised Machine Learning Models on Diagnosing Breast Cancer. Annals of Medicine and Surgery, 62, 53–64. https://doi.org/10.1016/j.amsu.2020.12.043
Alhenawi, E., Al-Sayyed, R., Hudaib, A., & Mirjalili, S. (2022). Feature selection methods on gene expression microarray data for cancer classification: A systematic review. Computers in Biology and Medicine, 140, 105051. https://doi.org/10.1016/j.compbiomed.2021.105051
Ali, M., & Aittokallio, T. (2019). Machine learning and feature selection for drug response prediction in precision oncology applications. Biophysical Reviews, 11(1), 31–39. https://doi.org/10.1007/s12551-018-0446-z
Almazrua, H., & Alshamlan, H. (2022). A Comprehensive Survey of Recent Hybrid Feature Selection Methods in Cancer Microarray Gene Expression Data. IEEE Access, 10, 71427–71449. https://doi.org/10.1109/ACCESS.2022.3185226
Almugren, N., & Alshamlan, H. (2019). A Survey on Hybrid Feature Selection Methods in Microarray Gene Expression Data for Cancer Classification. IEEE Access, 7, 78533–78548. https://doi.org/10.1109/ACCESS.2019.2922987
Bansal, M., Goyal, A., & Choudhary, A. (2022). A comparative analysis of K-Nearest Neighbor, Genetic, Support Vector Machine, Decision Tree, and Long Short Term Memory algorithms in machine learning. Decision Analytics Journal, 3, 100071. https://doi.org/10.1016/j.dajour.2022.100071
Basavegowda, H. S., & Dagnew, G. (2020). Deep learning approach for microarray cancer data classification. CAAI Transactions on Intelligence Technology, 5(1), 22–33. https://doi.org/10.1049/trit.2019.0028
Berry, M. W., Mohamed, A., & Yap, B. W. (Eds.). (2020). Supervised and Unsupervised Learning for Data Science. Springer International Publishing. https://doi.org/10.1007/978-3-030-22475-2
Biswas, N., Ali, M. M., Rahaman, M. A., Islam, M., Mia, Md. R., Azam, S., Ahmed, K., Bui, F. M., Al-Zahrani, F. A., & Moni, M. A. (2023). Machine Learning-Based Model to Predict Heart Disease in Early Stage Employing Different Feature Selection Techniques. BioMed Research International, 2023, 1–15. https://doi.org/10.1155/2023/6864343
Bommert, A., Welchowski, T., Schmid, M., & Rahnenführer, J. (2022). Benchmark of filter methods for feature selection in high-dimensional gene expression survival data. Briefings in Bioinformatics, 23(1), bbab354. https://doi.org/10.1093/bib/bbab354
Bouke, M. A., Abdullah, A., Frnda, J., Cengiz, K., & Salah, B. (2023). BukaGini: A Stability-Aware Gini Index Feature Selection Algorithm for Robust Model Performance. IEEE Access, 11, 59386–59396. https://doi.org/10.1109/ACCESS.2023.3284975
Burkart, N., & Huber, M. F. (2021). A Survey on the Explainability of Supervised Machine Learning. Journal of Artificial Intelligence Research, 70, 245–317. https://doi.org/10.1613/jair.1.12228
Ceriotti, M. (2019). Unsupervised machine learning in atomistic simulations, between predictions and understanding. The Journal of Chemical Physics, 150(15), 150901. https://doi.org/10.1063/1.5091842
Chen et al. - 2020—A novel selective naïve Bayes algorithm.pdf. (n.d.).
Chen, S., Webb, G. I., Liu, L., & Ma, X. (2020). A novel selective naïve Bayes algorithm. Knowledge-Based Systems, 192, 105361. https://doi.org/10.1016/j.knosys.2019.105361
Cho, H., Tong, F., You, S., Jung, S., Kim, W. H., & Kim, J. (2022). Prediction of the Immune Phenotypes of Bladder Cancer Patients for Precision Oncology. IEEE Open Journal of Engineering in Medicine and Biology, 3, 47–57. https://doi.org/10.1109/OJEMB.2022.3163533
Ferdous, M., Debnath, J., & Chakraborty, N. R. (2020). Machine Learning Algorithms in Healthcare: A Literature Survey. 2020 11th International Conference on Computing, Communication and Networking Technologies (ICCCNT), 1–6. https://doi.org/10.1109/ICCCNT49239.2020.9225642
Ghosh, M., Guha, R., Sarkar, R., & Abraham, A. (2020a). A wrapper-filter feature selection technique based on ant colony optimization. Neural Computing and Applications, 32(12), Article 12. https://doi.org/10.1007/s00521-019-04171-3
Ghosh, M., Guha, R., Sarkar, R., & Abraham, A. (2020b). A wrapper-filter feature selection technique based on ant colony optimization. Neural Computing and Applications, 32(12), 7839–7857. https://doi.org/10.1007/s00521-019-04171-3
Ghosh, P., Azam, S., Jonkman, M., Karim, A., Shamrat, F. M. J. M., Ignatious, E., Shultana, S., Beeravolu, A. R., & De Boer, F. (2021a). Efficient Prediction of Cardiovascular Disease Using Machine Learning Algorithms With Relief and LASSO Feature Selection Techniques. IEEE Access, 9, 19304–19326. https://doi.org/10.1109/ACCESS.2021.3053759
Ghosh, P., Azam, S., Jonkman, M., Karim, A., Shamrat, F. M. J. M., Ignatious, E., Shultana, S., Beeravolu, A. R., & De Boer, F. (2021b). Efficient Prediction of Cardiovascular Disease Using Machine Learning Algorithms With Relief and LASSO Feature Selection Techniques. IEEE Access, 9, 19304–19326. https://doi.org/10.1109/ACCESS.2021.3053759
H. Al-Baity, H., & Al-Mutlaq, N. (2021). A New Optimized Wrapper Gene Selection Method for Breast Cancer Prediction. Computers, Materials & Continua, 67(3), 3089–3106. https://doi.org/10.32604/cmc.2021.015291
Haq, A. U., Li, J. P., Saboor, A., Khan, J., Wali, S., Ahmad, S., Ali, A., Khan, G. A., & Zhou, W. (2021). Detection of Breast Cancer Through Clinical Data Using Supervised and Unsupervised Feature Selection Techniques. IEEE Access, 9, 22090–22105. https://doi.org/10.1109/ACCESS.2021.3055806
Hassan, N. S., Abdulazeez, A. M., Zeebaree, D. Q., & Hasan, D. A. (2021). Medical Images Breast Cancer Segmentation Based on K-Means Clustering Algorithm: A Review. Asian Journal of Research in Computer Science, 23–38. https://doi.org/10.9734/ajrcos/2021/v9i130212
Hossain, Md. A., Saiful Islam, S. M., Quinn, J. M. W., Huq, F., & Moni, M. A. (2019). Machine learning and bioinformatics models to identify gene expression patterns of ovarian cancer associated with disease progression and mortality. Journal of Biomedical Informatics, 100, 103313. https://doi.org/10.1016/j.jbi.2019.103313
Itoo, F., Meenakshi, & Singh, S. (2021). Comparison and analysis of logistic regression, Naïve Bayes and KNN machine learning algorithms for credit card fraud detection. International Journal of Information Technology, 13(4), 1503–1511. https://doi.org/10.1007/s41870-020-00430-y
Jiang, T., Gradus, J. L., & Rosellini, A. J. (2020). Supervised Machine Learning: A Brief Primer. Behavior Therapy, 51(5), 675–687. https://doi.org/10.1016/j.beth.2020.05.002
Jo, T. (2021). Machine Learning Foundations: Supervised, Unsupervised, and Advanced Learning. Springer International Publishing. https://doi.org/10.1007/978-3-030-65900-4
Kang, C., Huo, Y., Xin, L., Tian, B., & Yu, B. (2019a). Feature selection and tumor classification for microarray data using relaxed Lasso and generalized multi-class support vector machine. Journal of Theoretical Biology, 463, 77–91. https://doi.org/10.1016/j.jtbi.2018.12.010
Kang, C., Huo, Y., Xin, L., Tian, B., & Yu, B. (2019b). Feature selection and tumor classification for microarray data using relaxed Lasso and generalized multi-class support vector machine. Journal of Theoretical Biology, 463, 77–91. https://doi.org/10.1016/j.jtbi.2018.12.010
Kegerreis, B., Catalina, M. D., Bachali, P., Geraci, N. S., Labonte, A. C., Zeng, C., Stearrett, N., Crandall, K. A., Lipsky, P. E., & Grammer, A. C. (2019). Machine learning approaches to predict lupus disease activity from gene expression data. Scientific Reports, 9(1), 9617. https://doi.org/10.1038/s41598-019-45989-0
Khalifa, N. E. M., Taha, M. H. N., Ezzat Ali, D., Slowik, A., & Hassanien, A. E. (2020a). Artificial Intelligence Technique for Gene Expression by Tumor RNA-Seq Data: A Novel Optimized Deep Learning Approach. IEEE Access, 8, 22874–22883. https://doi.org/10.1109/ACCESS.2020.2970210
Khalifa, N. E. M., Taha, M. H. N., Ezzat Ali, D., Slowik, A., & Hassanien, A. E. (2020b). Artificial Intelligence Technique for Gene Expression by Tumor RNA-Seq Data: A Novel Optimized Deep Learning Approach. IEEE Access, 8, 22874–22883. https://doi.org/10.1109/ACCESS.2020.2970210
Khan, Z., Naeem, M., Khalil, U., Khan, D. M., Aldahmani, S., & Hamraz, M. (2019). Feature Selection for Binary Classification Within Functional Genomics Experiments via Interquartile Range and Clustering. IEEE Access, 7, 78159–78169. https://doi.org/10.1109/ACCESS.2019.2922432
Khorshid, S. F., & Abdulazeez, A. M. (2021). BREAST CANCER DIAGNOSIS BASED ON K-NEAREST NEIGHBORS: A REVIEW.
Kishore, A., Venkataramana, L., Prasad, D. V. V., Mohan, A., & Jha, B. (2023). Enhancing the prediction of IDC breast cancer staging from gene expression profiles using hybrid feature selection methods and deep learning architecture. Medical & Biological Engineering & Computing, 61(11), 2895–2919. https://doi.org/10.1007/s11517-023-02892-1
Kurniabudi, Stiawan, D., Darmawijoyo, Bin Idris, M. Y., Bamhdi, A. M., & Budiarto, R. (2020). CICIDS-2017 Dataset Feature Analysis With Information Gain for Anomaly Detection. IEEE Access, 8, 132911–132921. https://doi.org/10.1109/ACCESS.2020.3009843
Lindholm, A., Wahlström, N., Lindsten, F., & Schön, T. B. (n.d.). Supervised Machine Learning.
Liu, H., Zhou, M., & Liu, Q. (2019). An embedded feature selection method for imbalanced data classification. IEEE/CAA Journal of Automatica Sinica, 6(3), 703–715. https://doi.org/10.1109/JAS.2019.1911447
Liu, X., Zhu, X., Li, M., Wang, L., Zhu, E., Liu, T., Kloft, M., Shen, D., Yin, J., & Gao, W. (2018). Multiple Kernel k-means with Incomplete Kernels.
Mahendran, N., & P M, D. R. V. (2022). A deep learning framework with an embedded-based feature selection approach for the early detection of the Alzheimer’s disease. Computers in Biology and Medicine, 141, 105056. https://doi.org/10.1016/j.compbiomed.2021.105056
Mahesh, B. (2018). Machine Learning Algorithms—A Review. 9(1).
Mallick, P. K., Mohapatra, S. K., Chae, G.-S., & Mohanty, M. N. (2023). Convergent learning–based model for leukemia classification from gene expression. Personal and Ubiquitous Computing, 27(3), 1103–1110. https://doi.org/10.1007/s00779-020-01467-3
Maniruzzaman, Md., Jahanur Rahman, Md., Ahammed, B., Abedin, Md. M., Suri, H. S., Biswas, M., El-Baz, A., Bangeas, P., Tsoulfas, G., & Suri, J. S. (2019). Statistical characterization and classification of colon microarray gene expression data using multiple machine learning paradigms. Computer Methods and Programs in Biomedicine, 176, 173–193. https://doi.org/10.1016/j.cmpb.2019.04.008
Mohammed, N. N., & Abdulazeez, A. M. (2017). Gene clustering with partition around mediods algorithm based on weighted and normalized mahalanobis distance. 2017 International Conference on Intelligent Informatics and Biomedical Sciences (ICIIBMS), 140–145. https://doi.org/10.1109/ICIIBMS.2017.8279707
Ngiam, K. Y., & Khor, I. W. (2019). Big data and machine learning algorithms for health-care delivery. The Lancet Oncology, 20(5), e262–e273. https://doi.org/10.1016/S1470-2045(19)30149-4
Pinal-Fernandez, I., Casal-Dominguez, M., Derfoul, A., Pak, K., Miller, F. W., Milisenda, J. C., Grau-Junyent, J. M., Selva-O’Callaghan, A., Carrion-Ribas, C., Paik, J. J., Albayda, J., Christopher-Stine, L., Lloyd, T. E., Corse, A. M., & Mammen, A. L. (2020). Machine learning algorithms reveal unique gene expression profiles in muscle biopsies from patients with different types of myositis. Annals of the Rheumatic Diseases, 79(9), 1234–1242. https://doi.org/10.1136/annrheumdis-2019-216599
Rahat, A. M., Kahir, A., & Masum, A. K. M. (2019). Comparison of Naive Bayes and SVM Algorithm based on Sentiment Analysis Using Review Dataset. 2019 8th International Conference System Modeling and Advancement in Research Trends (SMART), 266–270. https://doi.org/10.1109/SMART46866.2019.9117512
Ray, S. (n.d.). A Quick Review of Machine Learning Algorithms.
Sarker, I. H. (2021). Machine Learning: Algorithms, Real-World Applications and Research Directions. SN Computer Science, 2(3), 160. https://doi.org/10.1007/s42979-021-00592-x
Saxena, R., Sharma, S. K., Gupta, M., & Sampada, G. C. (2022). A Novel Approach for Feature Selection and Classification of Diabetes Mellitus: Machine Learning Methods. Computational Intelligence and Neuroscience, 2022, 1–11. https://doi.org/10.1155/2022/3820360
Scheurer, M. S., & Slager, R.-J. (2020). Unsupervised Machine Learning and Band Topology. Physical Review Letters, 124(22), 226401. https://doi.org/10.1103/PhysRevLett.124.226401
Seal, D. B., Das, V., Goswami, S., & De, R. K. (2020a). Estimating gene expression from DNA methylation and copy number variation: A deep learning regression model for multi-omics integration. Genomics, 112(4), Article 4. https://doi.org/10.1016/j.ygeno.2020.03.021
Seal, D. B., Das, V., Goswami, S., & De, R. K. (2020b). Estimating gene expression from DNA methylation and copy number variation: A deep learning regression model for multi-omics integration. Genomics, 112(4), 2833–2841. https://doi.org/10.1016/j.ygeno.2020.03.021
Sen, P. C., Hajra, M., & Ghosh, M. (2020). Supervised Classification Algorithms in Machine Learning: A Survey and Review. In J. K. Mandal & D. Bhattacharya (Eds.), Emerging Technology in Modelling and Graphics (Vol. 937, pp. 99–111). Springer Singapore. https://doi.org/10.1007/978-981-13-7403-6_11
Shaban, W. M., Rabie, A. H., Saleh, A. I., & Abo-Elsoud, M. A. (2020a). A new COVID-19 Patients Detection Strategy (CPDS) based on hybrid feature selection and enhanced KNN classifier. Knowledge-Based Systems, 205, 106270. https://doi.org/10.1016/j.knosys.2020.106270
Shaban, W. M., Rabie, A. H., Saleh, A. I., & Abo-Elsoud, M. A. (2020b). A new COVID-19 Patients Detection Strategy (CPDS) based on hybrid feature selection and enhanced KNN classifier. Knowledge-Based Systems, 205, 106270. https://doi.org/10.1016/j.knosys.2020.106270
Shokrzade, A., Ramezani, M., Akhlaghian Tab, F., & Abdulla Mohammad, M. (2021). A novel extreme learning machine based kNN classification method for dealing with big data. Expert Systems with Applications, 183, 115293. https://doi.org/10.1016/j.eswa.2021.115293
Sinaga, K. P., & Yang, M.-S. (2020). Unsupervised K-Means Clustering Algorithm. IEEE Access, 8, 80716–80727. https://doi.org/10.1109/ACCESS.2020.2988796
Singh, D., Climente-González, H., Petrovich, M., Kawakami, E., & Yamada, M. (2020). FsNet: Feature Selection Network on High-dimensional Biological Data (arXiv:2001.08322). arXiv. http://arxiv.org/abs/2001.08322
Solorio-Fernández, S., Carrasco-Ochoa, J. A., & Martínez-Trinidad, J. Fco. (2020). A review of unsupervised feature selection methods. Artificial Intelligence Review, 53(2), 907–948. https://doi.org/10.1007/s10462-019-09682-y
Srinivasa, K. G., Siddesh, G. M., & Manisekhar, S. R. (Eds.). (2020). Statistical Modelling and Machine Learning Principles for Bioinformatics Techniques, Tools, and Applications. Springer Singapore. https://doi.org/10.1007/978-981-15-2445-5
Sun, L., Zhang, X., Qian, Y., Xu, J., & Zhang, S. (2019a). Feature selection using neighborhood entropy-based uncertainty measures for gene expression data classification. Information Sciences, 502, 18–41. https://doi.org/10.1016/j.ins.2019.05.072
Sun, L., Zhang, X., Qian, Y., Xu, J., & Zhang, S. (2019b). Feature selection using neighborhood entropy-based uncertainty measures for gene expression data classification. Information Sciences, 502, 18–41. https://doi.org/10.1016/j.ins.2019.05.072
Surya and Subbulakshmi—2019—Sentimental Analysis using Naive Bayes Classifier.pdf. (n.d.).
Tabl, A. A., Alkhateeb, A., ElMaraghy, W., Rueda, L., & Ngom, A. (2019a). A Machine Learning Approach for Identifying Gene Biomarkers Guiding the Treatment of Breast Cancer. Frontiers in Genetics, 10. https://www.frontiersin.org/articles/10.3389/fgene.2019.00256
Tabl, A. A., Alkhateeb, A., ElMaraghy, W., Rueda, L., & Ngom, A. (2019b). A Machine Learning Approach for Identifying Gene Biomarkers Guiding the Treatment of Breast Cancer. Frontiers in Genetics, 10. https://www.frontiersin.org/articles/10.3389/fgene.2019.00256
Taunk, K., De, S., Verma, S., & Swetapadma, A. (2019). A Brief Review of Nearest Neighbor Algorithm for Learning and Classification. 2019 International Conference on Intelligent Computing and Control Systems (ICCS), 1255–1260. https://doi.org/10.1109/ICCS45141.2019.9065747
Tharwat, A. (2021). Independent component analysis: An introduction. Applied Computing and Informatics, 17(2), 222–249. https://doi.org/10.1016/j.aci.2018.08.006
Toğaçar, M., Ergen, B., Cömert, Z., & Özyurt, F. (2020). A Deep Feature Learning Model for Pneumonia Detection Applying a Combination of mRMR Feature Selection and Machine Learning Models. IRBM, 41(4), 212–222. https://doi.org/10.1016/j.irbm.2019.10.006
Uddin, S., Khan, A., Hossain, M. E., & Moni, M. A. (2019). Comparing different supervised machine learning algorithms for disease prediction. BMC Medical Informatics and Decision Making, 19(1), 281. https://doi.org/10.1186/s12911-019-1004-8
Usama, M., Qadir, J., Raza, A., Arif, H., Yau, K. A., Elkhatib, Y., Hussain, A., & Al-Fuqaha, A. (2019). Unsupervised Machine Learning for Networking: Techniques, Applications and Research Challenges. IEEE Access, 7, 65579–65615. https://doi.org/10.1109/ACCESS.2019.2916648
Wu, J., & Hicks, C. (2021). Breast Cancer Type Classification Using Machine Learning. Journal of Personalized Medicine, 11(2), 61. https://doi.org/10.3390/jpm11020061
Xia, H., Akay, Y. M., & Akay, M. (2021). Selecting Relevant Genes From Microarray Datasets Using a Random Forest Model. IEEE Access, 9, 97813–97821. https://doi.org/10.1109/ACCESS.2021.3092368
Xing, W., & Bei, Y. (2020). Medical Health Big Data Classification Based on KNN Classification Algorithm. IEEE Access, 8, 28808–28819. https://doi.org/10.1109/ACCESS.2019.2955754
Yuan, A., You, M., He, D., & Li, X. (2022). Convex Non-Negative Matrix Factorization With Adaptive Graph for Unsupervised Feature Selection. IEEE Transactions on Cybernetics, 52(6), 5522–5534. https://doi.org/10.1109/TCYB.2020.3034462
Yuan, C., & Yang, H. (2019). Research on K-Value Selection Method of K-Means Clustering Algorithm. J, 2(2), 226–235. https://doi.org/10.3390/j2020016
Yuan, F., Lu, L., & Zou, Q. (2020). Analysis of gene expression profiles of lung cancer subtypes with machine learning algorithms. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1866(8), 165822. https://doi.org/10.1016/j.bbadis.2020.165822
Zeebaree, D. Q., Haron, H., & Abdulazeez, A. M. (2018). Gene Selection and Classification of Microarray Data Using Convolutional Neural Network. 2018 International Conference on Advanced Science and Engineering (ICOASE), 145–150. https://doi.org/10.1109/ICOASE.2018.8548836
Zhang, J., Xu, D., Hao, K., Zhang, Y., Chen, W., Liu, J., Gao, R., Wu, C., & De Marinis, Y. (2021). FS–GBDT: Identification multicancer-risk module via a feature selection algorithm by integrating Fisher score and GBDT. Briefings in Bioinformatics, 22(3), bbaa189. https://doi.org/10.1093/bib/bbaa189
Zulfiqar, H., Huang, Q.-L., Lv, H., Sun, Z.-J., Dao, F.-Y., & Lin, H. (2022). Deep-4mCGP: A Deep Learning Approach to Predict 4mC Sites in Geobacter pickeringii by Using Correlation-Based Feature Selection Technique. International Journal of Molecular Sciences, 23(3), 1251. https://doi.org/10.3390/ijms23031251
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