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We perform global sensitivity analysis using partial rank correlation coefficients to identify key parameters influencing transmission. The model\u2019s bifurcation structure is examined through the basic reproduction number RM0, revealing both forward and backward bifurcations that highlight threshold behavior and the potential for complex endemic dynamics. For real-time forecasting, we incorporate prior knowledge of mpox dynamics into machine learning models, ARNN (Autoregressive Neural Network), ARIMA (Autoregressive Integrated Moving Average), and LSTM (Long Short-Term Memory), achieving improved predictive accuracy over traditional methods. These epidemic-informed models benefit from mechanistic insights, enhancing their responsiveness to changing trends. Our results emphasize the importance of timely treatment, hygiene, and vaccination in mitigating mpox spread. The integrated modeling and the forecasting framework provide valuable tools for anticipating outbreaks and informing public health strategies.<\/jats:p>","DOI":"10.1063\/5.0299032","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T14:09:42Z","timestamp":1763042982000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["Threshold dynamics and epidemic-informed machine learning for forecasting of mpox: A U.S. case study"],"prefix":"10.1063","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7810-2553","authenticated-orcid":false,"given":"S.","family":"Nivetha","sequence":"first","affiliation":[{"name":"Department of Mathematics, School of Advanced Sciences, Vellore Institute of Technology 1 , Chennai Campus, Chennai 600127, Tamil Nadu,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2312-5263","authenticated-orcid":false,"given":"Parthasakha","family":"Das","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Rajiv Gandhi National Institute of Youth Development 2 , Sriperumbudur 602105, Tamil Nadu,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9652-2409","authenticated-orcid":false,"given":"Mini","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Mathematics, School of Advanced Sciences, Vellore Institute of Technology 1 , Chennai Campus, Chennai 600127, Tamil Nadu,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"317","published-online":{"date-parts":[[2025,11,13]]},"reference":[{"key":"2025111309093700100_c1"},{"key":"2025111309093700100_c2"},{"key":"2025111309093700100_c3","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1140\/epjs\/s11734-024-01346-5","article-title":"Impact of surveillance in human-to-human transmission of monkeypox virus","volume":"234","year":"2025","journal-title":"Eur. 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