{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T08:25:33Z","timestamp":1769847933280,"version":"3.49.0"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>Animal models of atherosclerosis are used extensively to interrogate molecular mechanisms in serial fashion. We tested whether a novel systems biology approach to integration of preclinical data identifies novel pathways and regulators in human disease.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results:<\/jats:title>\n            <jats:p>\n              Of 716 articles published in\n              <jats:italic>ATVB<\/jats:italic>\n              from 1995 to 2019 using the apolipoprotein E knockout mouse to study atherosclerosis, data were extracted from 360 unique studies in which a gene was experimentally perturbed to impact plaque size or composition and analyzed using Ingenuity Pathway Analysis software. TREM1 (triggering receptor expressed on myeloid cells) signaling and LXR\/RXR (liver X receptor\/retinoid X receptor) activation were identified as the top atherosclerosis-associated pathways in mice (both\n              <jats:italic>P<\/jats:italic>\n              &lt;1.93\u00d710\n              <jats:sup>\u2212<\/jats:sup>\n              <jats:sup>4<\/jats:sup>\n              , TREM1 implicated early and LXR\/RXR in late atherogenesis). The top upstream regulatory network in mice (sc-58125, a COX2 inhibitor) linked 64.0% of the genes into a single network. The pathways and networks identified in mice were interrogated by testing for associations between the genetically predicted gene expression of each mouse pathway-identified human homolog with clinical atherosclerosis in a cohort of 88\u2009660 human subjects. Homologous human pathways and networks were significantly enriched for gene-atherosclerosis associations (empirical\n              <jats:italic>P<\/jats:italic>\n              &lt;0.01 for TREM1 and LXR\/RXR pathways and COX2 network). This included 12(60.0%) TREM1 pathway genes, 15(53.6%) LXR\/RXR pathway genes, and 67(49.3%) COX2 network genes. Mouse analyses predicted, and human study validated, the strong association of COX2 expression (\n              <jats:italic>PTGS2<\/jats:italic>\n              ) with increased likelihood of atherosclerosis (odds ratio, 1.68 per SD of genetically predicted gene expression;\n              <jats:italic>P<\/jats:italic>\n              =1.07\u00d710\n              <jats:sup>\u2212<\/jats:sup>\n              <jats:sup>6<\/jats:sup>\n              ).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>PRESCIANT (Preclinical Science Integration and Translation) leverages published preclinical investigations to identify high-confidence pathways, networks, and regulators of human disease.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.121.317071","type":"journal-article","created":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T10:00:21Z","timestamp":1636624821000},"page":"35-48","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Systems Approach to Integrating Preclinical Apolipoprotein E-Knockout Investigations Reveals Novel Etiologic Pathways and Master Atherosclerosis Network in Humans"],"prefix":"10.1161","volume":"42","author":[{"given":"Megan M.","family":"Shuey","sequence":"first","affiliation":[{"name":"Department of Medicine (M.M.S., J.R., Q.S.W., J.A.B.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel R.","family":"Xiang","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute (R.R.X., M.E.M., B.V.C., Y.W., N.C., A.S., I.Z.J.), Tufts Medical Center, Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9761-7263","authenticated-orcid":true,"given":"M. Elizabeth","family":"Moss","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute (R.R.X., M.E.M., B.V.C., Y.W., N.C., A.S., I.Z.J.), Tufts Medical Center, Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brigett V.","family":"Carvajal","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute (R.R.X., M.E.M., B.V.C., Y.W., N.C., A.S., I.Z.J.), Tufts Medical Center, Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yihua","family":"Wang","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute (R.R.X., M.E.M., B.V.C., Y.W., N.C., A.S., I.Z.J.), Tufts Medical Center, Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1853-0056","authenticated-orcid":true,"given":"Nicholas","family":"Camarda","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute (R.R.X., M.E.M., B.V.C., Y.W., N.C., A.S., I.Z.J.), Tufts Medical Center, Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Fabbri","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics (D.F., P.R.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Protiva","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics (D.F., P.R.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0966-3292","authenticated-orcid":true,"given":"Jacob","family":"Ramsey","sequence":"additional","affiliation":[{"name":"Department of Medicine (M.M.S., J.R., Q.S.W., J.A.B.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4719-5792","authenticated-orcid":true,"given":"Alec","family":"Stepanian","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute (R.R.X., M.E.M., B.V.C., Y.W., N.C., A.S., I.Z.J.), Tufts Medical Center, Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Sebastiani","sequence":"additional","affiliation":[{"name":"Institute for Clinical Research and Health Policy Studies (P.S.), Tufts Medical Center, Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3899-0313","authenticated-orcid":true,"given":"Quinn S.","family":"Wells","sequence":"additional","affiliation":[{"name":"Department of Medicine (M.M.S., J.R., Q.S.W., J.A.B.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8332-8439","authenticated-orcid":true,"given":"Joshua A.","family":"Beckman","sequence":"additional","affiliation":[{"name":"Department of Medicine (M.M.S., J.R., Q.S.W., J.A.B.), Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9300-1253","authenticated-orcid":true,"given":"Iris Z.","family":"Jaffe","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute (R.R.X., M.E.M., B.V.C., Y.W., N.C., A.S., I.Z.J.), Tufts Medical Center, Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.110.220574"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90362-g"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.10.4471"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1411543"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATV.0000000000000062"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt703"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2008.89"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq126"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu197"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3643"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3656"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1847"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature24277"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1262110"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz1776"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-0706-2"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0345-7"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3367"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.neo.7900177"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/jf026056p"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-05-0440"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707914"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.163.2.963"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0098165"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.109.198762"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000014927.74465.7f"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/jcpt.12484"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-012-1335-1"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.c7086"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa050493"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2013.10.017"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.00-0716fje"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.4103\/1735-1995.193507"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.22122\/arya.v16i4.2011"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-997-0015-z"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1089\/acm.2018.0226"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.11613\/BM.2017.030201"}],"container-title":["Arteriosclerosis, Thrombosis, and Vascular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/ATVBAHA.121.317071","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T23:49:40Z","timestamp":1715557780000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/ATVBAHA.121.317071"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1]]},"references-count":37,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,1]]}},"alternative-id":["10.1161\/ATVBAHA.121.317071"],"URL":"https:\/\/doi.org\/10.1161\/atvbaha.121.317071","relation":{},"ISSN":["1079-5642","1524-4636"],"issn-type":[{"value":"1079-5642","type":"print"},{"value":"1524-4636","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1]]},"assertion":[{"value":"2021-08-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-10-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-11-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}