{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T20:34:35Z","timestamp":1772138075468,"version":"3.50.1"},"reference-count":88,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Sciences Foundation of China","doi-asserted-by":"crossref","award":["82204118"],"award-info":[{"award-number":["82204118"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province","award":["2020E10004"],"award-info":[{"award-number":["2020E10004"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35HG010718"],"award-info":[{"award-number":["R35HG010718"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH\/NHGRI","award":["R01HG011138"],"award-info":[{"award-number":["R01HG011138"]}]},{"name":"NIH\/NIA","award":["R56AG068026"],"award-info":[{"award-number":["R56AG068026"]}]},{"name":"NIH\/NIGMS","award":["R01GM140287"],"award-info":[{"award-number":["R01GM140287"]}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>Drug repositioning presents a streamlined and cost-efficient way to expand the range of therapeutic possibilities. Drugs with human genetic evidence are more likely to advance successfully through clinical trials toward Food and Drug Administration approval. Single gene-based drug repositioning methods have been implemented, but approaches leveraging a broad spectrum of molecular signatures remain underexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We propose a framework called \u201cTranscriptome-informed Reversal Distance\u201d (TReD) that embeds the disease signatures and drug response profiles into a high-dimensional normed space to quantify the reversal potential of candidate drugs in a disease-related cell-based screening. We applied TReD to COVID-19, type 2 diabetes, and Alzheimer\u2019s disease (AD), identifying 36, 16, and 11 candidate drugs, respectively. Among these, literature supports 69% (25\/36), 31% (5\/16), and 64% (7\/11) of the drugs, with clinical trials conducted for seven COVID-19 candidates and three AD candidates. In summary, we propose a comprehensive genetics-anchored framework integrating population-level signatures and cell-based screening that has the potential to accelerate the search for new therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>Source code and datasets considered in this study are available at Github (https:\/\/github.com\/zdangm\/TReD). An archived snapshot is deposited at Zenodo (https:\/\/doi.org\/10.5281\/zenodo.16791909).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btaf498","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T11:31:51Z","timestamp":1757417511000},"source":"Crossref","is-referenced-by-count":0,"title":["Integrating population-level and cell-based signatures for drug repositioning"],"prefix":"10.1093","volume":"41","author":[{"given":"Chunfeng","family":"He","sequence":"first","affiliation":[{"name":"The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine , 310058, HangZhou,","place":["China"]},{"name":"The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University , 310058, HangZhou,","place":["China"]}]},{"given":"Yue","family":"Xu","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine , 310058, HangZhou,","place":["China"]},{"name":"The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University , 310058, HangZhou,","place":["China"]}]},{"given":"Yuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center , Nashville, TN 37232,","place":["United States"]}]},{"given":"Jiayao","family":"Fan","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine , 310058, HangZhou,","place":["China"]},{"name":"The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Zhejiang University , 310058, HangZhou,","place":["China"]}]},{"given":"Chunxiao","family":"Cheng","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine , 310058, HangZhou,","place":["China"]}]},{"given":"Ran","family":"Meng","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine , 310058, HangZhou,","place":["China"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9938-3627","authenticated-orcid":false,"given":"Lang","family":"Wu","sequence":"additional","affiliation":[{"name":"Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa , Honolulu, HI 96813,","place":["United States"]}]},{"given":"Ruiyuan","family":"Pan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University , Guangzhou 510515,","place":["China"]},{"name":"Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University , Guangzhou 510515,","place":["China"]},{"name":"Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Southern Medical University , Guangzhou 510515,","place":["China"]},{"name":"Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University , Guangzhou 510515,","place":["China"]}]},{"given":"Ravi V","family":"Shah","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Vanderbilt University Medical Center , Nashville, TN 37232,","place":["United States"]}]},{"given":"Eric R","family":"Gamazon","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Vanderbilt University Medical Center , Nashville, TN 37232,","place":["United States"]},{"name":"Vanderbilt Diabetes Center, Vanderbilt University Medical Center , Nashville, TN 37232,","place":["United 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