{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:43:01Z","timestamp":1790779381993,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,10,28]],"date-time":"2023-10-28T00:00:00Z","timestamp":1698451200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 CA262147"],"award-info":[{"award-number":["R01 CA262147"]}]},{"name":"NIH","award":["CMMI 2224708"],"award-info":[{"award-number":["CMMI 2224708"]}]},{"DOI":"10.13039\/100000001","name":"NSF","doi-asserted-by":"publisher","award":["R01 CA262147"],"award-info":[{"award-number":["R01 CA262147"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"NSF","doi-asserted-by":"publisher","award":["CMMI 2224708"],"award-info":[{"award-number":["CMMI 2224708"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MLSC Bit-to-Bites program","award":["R01 CA262147"],"award-info":[{"award-number":["R01 CA262147"]}]},{"name":"MLSC Bit-to-Bites program","award":["CMMI 2224708"],"award-info":[{"award-number":["CMMI 2224708"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Previously, the analysis of atomic force microscopy (AFM) images allowed us to distinguish normal from cancerous\/precancerous human epithelial cervical cells using only the fractal dimension parameter. High-resolution maps of adhesion between the AFM probe and the cell surface were used in that study. However, the separation of cancerous and precancerous cells was rather poor (the area under the curve (AUC) was only 0.79, whereas the accuracy, sensitivity, and specificity were 74%, 58%, and 84%, respectively). At the same time, the separation between premalignant and malignant cells is the most significant from a clinical point of view. Here, we show that the introduction of machine learning methods for the analysis of adhesion maps allows us to distinguish precancerous and cancerous cervical cells with rather good precision (AUC, accuracy, sensitivity, and specificity are 0.93, 83%, 92%, and 78%, respectively). Substantial improvement in sensitivity is significant because of the unmet need in clinical practice to improve the screening of cervical cancer (a relatively low specificity can be compensated by combining this approach with other currently existing screening methods). The random forest decision tree algorithm was utilized in this study. The analysis was carried out using the data of six precancerous primary cell lines and six cancerous primary cell lines, each derived from different humans. The robustness of the classification was verified using K-fold cross-validation (K = 500). The results are statistically significant at p &lt; 0.0001. Statistical significance was determined using the random shuffle method as a control.<\/jats:p>","DOI":"10.3390\/cells12212536","type":"journal-article","created":{"date-parts":[[2023,10,30]],"date-time":"2023-10-30T09:27:28Z","timestamp":1698658048000},"page":"2536","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Machine Learning Allows for Distinguishing Precancerous and Cancerous Human Epithelial Cervical Cells Using High-Resolution AFM Imaging of Adhesion Maps"],"prefix":"10.3390","volume":"12","author":[{"given":"Mikhail","family":"Petrov","sequence":"first","affiliation":[{"name":"Department of Mechanical Engineering, Tufts University, Medford, MA 02155, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6260-4326","authenticated-orcid":false,"given":"Igor","family":"Sokolov","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, Tufts University, Medford, MA 02155, USA"},{"name":"Departments of Physics and Biomedical Engineering, Tufts University, Medford, MA 02155, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.ygyno.2007.03.016","article-title":"Human papillomavirus (HPV) test and PAP smear as predictors of outcome in conservatively treated adenocarcinoma in situ (AIS) of the uterine cervix","volume":"106","author":"Costa","year":"2007","journal-title":"Gynecol. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1002\/dc.20994","article-title":"Hematologic malignancies of the female genital tract diagnosed on liquid-based Pap test: Cytomorphologic features and review of differential diagnoses","volume":"37","author":"Hanley","year":"2009","journal-title":"Diagn. Cytopathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1002\/dc.20267","article-title":"\u201cFruiting body\u201d of Aspergillus species in a routine cervico-vaginal smear (Pap test)","volume":"33","author":"Hoda","year":"2005","journal-title":"Diagn. Cytopathol."},{"key":"ref_4","first-page":"1431","article-title":"Diagnostic approach for precancerous and early invasive cancerous lesions of the uterine cervix","volume":"33","author":"Grubisic","year":"2009","journal-title":"Coll. Antropol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1097\/00130404-200309000-00004","article-title":"The epidemiology of cervical cancer","volume":"9","author":"Franco","year":"2003","journal-title":"Cancer J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"342","DOI":"10.3322\/canjclin.52.6.342","article-title":"American Cancer Society guideline for the early detection of cervical neoplasia and cancer","volume":"52","author":"Saslow","year":"2002","journal-title":"CA Cancer J. Clin."},{"key":"ref_7","unstructured":"(2023, August 08). Available online: https:\/\/www.mass.gov\/doc\/cervical-cancer-in-massachusetts-2004-2014\/download."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"321","DOI":"10.3322\/caac.21628","article-title":"Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society","volume":"70","author":"Fontham","year":"2020","journal-title":"Ca-Cancer J. Clin."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/S1470-2045(11)70334-5","article-title":"How might HPV testing be integrated into cervical screening?","volume":"13","author":"Katki","year":"2012","journal-title":"Lancet Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1002\/(SICI)1097-0142(19990825)87:4<178::AID-CNCR3>3.0.CO;2-1","article-title":"Observer variation in cytologic grading for cervical dysplasia of Papanicolaou smears with the PAPNET testing system","volume":"87","author":"Doornewaard","year":"1999","journal-title":"Cancer"},{"key":"ref_11","first-page":"310","article-title":"Fractals in pathology: Are they really useful?","volume":"87","author":"Losa","year":"1995","journal-title":"Pathologica"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6484","DOI":"10.1073\/pnas.0501207102","article-title":"Nanoscale visualization and characterization of Myxococcus xanthus cells with atomic force microscopy","volume":"102","author":"Pelling","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/35078583","article-title":"Direct, high-resolution measurement of furrow stiffening during division of adherent cells","volume":"3","author":"Matzke","year":"2001","journal-title":"Nat. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.actbio.2007.04.002","article-title":"Biomechanics and biophysics of cancer cells","volume":"3","author":"Suresh","year":"2007","journal-title":"Acta Biomater."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0167-4889(01)00125-2","article-title":"The effect of chitosan on stiffness and glycolytic activity of human bladder cells","volume":"1540","author":"Lekka","year":"2001","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1002\/smll.200900434","article-title":"Towards nonspecific detection of malignant cervical cells with fluorescent silica beads","volume":"5","author":"Iyer","year":"2009","journal-title":"Small"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/nnano.2009.77","article-title":"AFM Detects Differences in the Surface Brush on Normal and Cancerous Cervical Cells","volume":"4","author":"Iyer","year":"2009","journal-title":"Nat. Nanotechnol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"033019","DOI":"10.1088\/1367-2630\/17\/3\/033019","article-title":"Emergence of fractal geometry on the surface of human cervical epithelial cells during progression towards cancer","volume":"17","author":"Dokukin","year":"2015","journal-title":"N. J. Phys."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"028101","DOI":"10.1103\/PhysRevLett.107.028101","article-title":"Cell Surface as a Fractal: Normal and Cancerous Cervical Cells Demonstrate Different Fractal Behavior of Surface Adhesion Maps at the Nanoscale","volume":"107","author":"Dokukin","year":"2011","journal-title":"Phys. Rev. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s12013-012-9345-2","article-title":"Physical Labeling of Papillomavirus-Infected, Immortal, and Cancerous Cervical Epithelial Cells Reveal Surface Changes at Immortal Stage","volume":"63","author":"Iyer","year":"2012","journal-title":"Cell Biochem. Biophys."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Origoni, M., Cantatore, F., Sopracordevole, F., Clemente, N., Spinillo, A., Gardella, B., De Vincenzo, R., Ricci, C., Landoni, F., and Di Meo, M.L. (2023). Colposcopy Accuracy and Diagnostic Performance: A Quality Control and Quality Assurance Survey in Italian Tertiary-Level Teaching and Academic Institutions-The Italian Society of Colposcopy and Cervico-Vaginal Pathology (SICPCV). Diagnostics, 13.","DOI":"10.3390\/diagnostics13111906"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhou, B., Khosla, A., Lapedriza, A., Oliva, A., and Torralba, A. (2016, January 27\u201330). Learning Deep Features for Discriminative Localization. Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition, Las Vegas, NV, USA.","DOI":"10.1109\/CVPR.2016.319"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1109\/TPAMI.2017.2711011","article-title":"NetVLAD: CNN Architecture for Weakly Supervised Place Recognition","volume":"40","author":"Arandjelovic","year":"2018","journal-title":"IEEE Trans. Pattern Anal. Mach. Intell."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"878","DOI":"10.3762\/bjnano.12.66","article-title":"The role of convolutional neural networks in scanning probe microscopy: A review","volume":"12","author":"Azuri","year":"2021","journal-title":"Beilstein J. Nanotechnol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1080\/21681163.2018.1427148","article-title":"The transition module: A method for preventing overfitting in convolutional neural networks","volume":"7","author":"Akbar","year":"2019","journal-title":"Comput. Methods Biomech. Biomed. Eng. Imaging Vis."},{"key":"ref_26","unstructured":"Fausett, L.V. (1994). Fundamentals of Neural Networks: Architectures, Algorithms, and Applications, Prentice-Hall."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s10994-015-5535-7","article-title":"Learning to identify relevant studies for systematic reviews using random forest and external information","volume":"102","author":"Khabsa","year":"2016","journal-title":"Mach. Learn."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1023\/A:1010933404324","article-title":"Random forests","volume":"45","author":"Breiman","year":"2001","journal-title":"Mach. Learn."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s10994-014-5451-2","article-title":"The effect of splitting on random forests","volume":"99","author":"Ishwaran","year":"2015","journal-title":"Mach. Learn."},{"key":"ref_30","unstructured":"(2019). Surface Texture (Surface Roughness, Waviness, and Lay) B46.1, ASME. [2019th ed.]."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"12920","DOI":"10.1073\/pnas.1816459115","article-title":"Noninvasive diagnostic imaging using machine-learning analysis of nanoresolution images of cell surfaces: Detection of bladder cancer","volume":"115","author":"Sokolov","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"35962","DOI":"10.1021\/acsami.3c06341","article-title":"Mechanical Way To Study Molecular Structure of Pericellular Layer","volume":"15","author":"Makarova","year":"2023","journal-title":"Acs Appl. Mater. Inter."},{"key":"ref_33","unstructured":"Meakin, P. (1998). Fractals, Scaling, and Growth Far from Equilibrium, Cambridge University Press."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"McCauley, J.L. (1993). Chaos, Dynamics, and Fractals: An Algorithmic Approach to Deterministic Chaos, Cambridge University Press.","DOI":"10.1017\/CBO9780511564154"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/16637","article-title":"The large-scale smoothness of the Universe","volume":"397","author":"Wu","year":"1999","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/294240a0","article-title":"Fractal dimensions of landscapes and other environmental data","volume":"294","author":"Burrough","year":"1981","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/314731a0","article-title":"Fractal dimension of vegetation and the distribution of arthropod body lengths","volume":"314","author":"Morse","year":"1985","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/353409a0","article-title":"Structure and growth mechanism of mineral dendrites","volume":"353","author":"Chopard","year":"1991","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1126\/science.216.4542.185","article-title":"Area-Perimeter Relation for Rain and Cloud Areas","volume":"216","author":"Lovejoy","year":"1982","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"E9","DOI":"10.1038\/nature05398","article-title":"Fractal Analysis: Revisiting Pollock\u2019s drip paintings","volume":"444","author":"Mathur","year":"2006","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Falconer, K.J. (1990). Fractal Geometry: Mathematical Foundations and Applications, Wiley.","DOI":"10.2307\/2532125"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Prasad, S., Rankine, A., Prasad, T., Song, P., Dokukin, M.E., Makarova, N., Backman, V., and Sokolov, I. (2021). Atomic Force Microscopy Detects the Difference in Cancer Cells of Different Neoplastic Aggressiveness via Machine Learning. Adv. NanoBiomed Res., 1.","DOI":"10.1002\/anbr.202000116"},{"key":"ref_43","first-page":"4620","article-title":"Characterization of normal human exocervical epithelial cells immortalized in vitro by papillomavirus types 16 and 18 DNA","volume":"48","author":"Woodworth","year":"1988","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"(2023, September 08). Available online: https:\/\/figshare.com\/articles\/dataset\/Data_for_the_surface_parameters_for_paper_M_E_Dokukin_i_et_al_i_2015_i_New_J_Phys_i_b_17_b_033019_b_DOI_b_10_1088_1367-2630_17_3_033019\/23810616.","DOI":"10.1088\/1367-2630\/17\/3\/033019"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1038\/nnano.2007.226","article-title":"An atomic force microscope tip designed to measure time-varying nanomechanical forces","volume":"2","author":"Sahin","year":"2007","journal-title":"Nat. Nanotechnol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/21\/2536\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:13:21Z","timestamp":1760130801000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/21\/2536"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,28]]},"references-count":45,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["cells12212536"],"URL":"https:\/\/doi.org\/10.3390\/cells12212536","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,28]]}}}