{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T16:21:54Z","timestamp":1775578914584,"version":"3.50.1"},"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T00:00:00Z","timestamp":1726704000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["AR052646"],"award-info":[{"award-number":["AR052646"]}]},{"name":"NIH","award":["HL167813"],"award-info":[{"award-number":["HL167813"]}]},{"name":"NIH","award":["NS047726"],"award-info":[{"award-number":["NS047726"]}]},{"name":"NIH","award":["NS127383"],"award-info":[{"award-number":["NS127383"]}]},{"name":"Lakeside Discovery"},{"name":"NCI","award":["P30 CA060553"],"award-info":[{"award-number":["P30 CA060553"]}]},{"name":"Chan Zuckerberg Initiative DAF","award":["2020-225578"],"award-info":[{"award-number":["2020-225578"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>The pathology in Duchenne muscular dystrophy (DMD) is characterized by degenerating muscle fibers, inflammation, fibro-fatty infiltrate, and edema, and these pathological processes replace normal healthy muscle tissue. The <jats:italic>mdx<\/jats:italic> mouse model is one of the most commonly used preclinical models to study DMD. Mounting evidence has emerged illustrating that muscle disease progression varies considerably in <jats:italic>mdx<\/jats:italic> mice, with inter-animal differences as well as intra-muscular differences in pathology in individual <jats:italic>mdx<\/jats:italic> mice. This variation is important to consider when conducting assessments of drug efficacy and in longitudinal studies. We developed a magnetic resonance imaging (MRI) segmentation and analysis pipeline to rapidly and non-invasively measure the severity of muscle disease in <jats:italic>mdx<\/jats:italic> mice.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Wildtype and <jats:italic>mdx<\/jats:italic> mice were imaged with MRI and T2 maps were obtained axially across the hindlimbs. A neural network was trained to rapidly and semi-automatically segment the muscle tissue, and the distribution of resulting T2 values was analyzed. Interdecile range and Pearson Skew were identified as biomarkers to quickly and accurately estimate muscle disease severity in mice.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>The semiautomated segmentation tool reduced image processing time approximately tenfold. Measures of Pearson skew and interdecile range based on that segmentation were repeatable and reflected muscle disease severity in healthy wildtype and diseased <jats:italic>mdx<\/jats:italic> mice based on both qualitative observation of images and correlation with Evans blue dye uptake.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Use of this rapid, non-invasive, semi-automated MR image segmentation and analysis pipeline has the potential to transform preclinical studies, allowing for pre-screening of dystrophic mice prior to study enrollment to ensure more uniform muscle disease pathology across treatment groups, improving study outcomes.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0310551","type":"journal-article","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T17:41:42Z","timestamp":1726767702000},"page":"e0310551","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Distribution of MRI-derived T2 values as a biomarker for in vivo rapid screening of phenotype severity in mdx mice"],"prefix":"10.1371","volume":"19","author":[{"given":"Emily A.","family":"Waters","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chad R.","family":"Haney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren A","family":"Vaught","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth 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Hoffman","year":"1987","journal-title":"Cell"},{"issue":"4","key":"pone.0310551.ref003","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1073\/pnas.81.4.1189","article-title":"X chromosome-linked muscular dystrophy (mdx) in the mouse.","volume":"81","author":"G Bulfield","year":"1984","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4912","key":"pone.0310551.ref004","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1126\/science.2662404","article-title":"The molecular basis of muscular dystrophy in the mdx mouse: a point mutation","volume":"244","author":"P Sicinski","year":"1989","journal-title":"Science"},{"issue":"3","key":"pone.0310551.ref005","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1242\/dmm.018424","article-title":"Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy","volume":"8","author":"JW McGreevy","year":"2015","journal-title":"Disease Models & Mechanisms."},{"issue":"5","key":"pone.0310551.ref006","doi-asserted-by":"crossref","first-page":"2414","DOI":"10.2353\/ajpath.2010.090887","article-title":"Genetic background affects properties of satellite cells and mdx phenotypes","volume":"176","author":"S Fukada","year":"2010","journal-title":"Am J Pathol"},{"issue":"2","key":"pone.0310551.ref007","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1083\/jcb.201510086","article-title":"Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype","volume":"213","author":"J Capote","year":"2016","journal-title":"J Cell Biol"},{"issue":"1","key":"pone.0310551.ref008","doi-asserted-by":"crossref","first-page":"14070","DOI":"10.1038\/s41598-020-70987-y","article-title":"The D2.mdx mouse as a preclinical model of the skeletal muscle pathology associated with Duchenne muscular dystrophy.","volume":"10","author":"DW Hammers","year":"2020","journal-title":"Sci Rep."},{"issue":"6","key":"pone.0310551.ref009","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.135703","article-title":"TGF-beta-driven muscle degeneration and failed regeneration underlie disease onset in a DMD mouse model.","volume":"5","author":"DA Mazala","year":"2020","journal-title":"JCI Insight."},{"issue":"7","key":"pone.0310551.ref010","doi-asserted-by":"crossref","first-page":"8110","DOI":"10.1096\/fj.201802488R","article-title":"Natural disease history of the D2-mdx mouse model for Duchenne muscular dystrophy","volume":"33","author":"M van Putten","year":"2019","journal-title":"FASEB J"},{"issue":"1","key":"pone.0310551.ref011","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1093\/hmg\/ddv460","article-title":"Effect of genetic background on the dystrophic phenotype in mdx mice","volume":"25","author":"WD Coley","year":"2016","journal-title":"Hum Mol Genet"},{"issue":"5","key":"pone.0310551.ref012","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1016\/j.ajpath.2011.07.009","article-title":"mdx((5)cv) mice manifest more severe muscle dysfunction and diaphragm force deficits than do mdx Mice","volume":"179","author":"N Beastrom","year":"2011","journal-title":"Am J Pathol"},{"issue":"6","key":"pone.0310551.ref013","doi-asserted-by":"crossref","first-page":"2520","DOI":"10.1002\/jcsm.13265","article-title":"Receptor interacting protein kinase-3 mediates both myopathy and cardiomyopathy in preclinical animal models of Duchenne muscular dystrophy.","volume":"14","author":"M Bencze","year":"2023","journal-title":"J Cachexia Sarcopenia Muscle."},{"issue":"1","key":"pone.0310551.ref014","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s13395-019-0207-0","article-title":"miR-146a deficiency does not aggravate muscular dystrophy in mdx mice.","volume":"9","author":"I Bronisz-Budzynska","year":"2019","journal-title":"Skelet Muscle."},{"issue":"1","key":"pone.0310551.ref015","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.nbd.2008.03.008","article-title":"Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy","volume":"31","author":"MD Grounds","year":"2008","journal-title":"Neurobiol Dis"},{"issue":"5","key":"pone.0310551.ref016","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1002\/mus.21211","article-title":"Preclinical drug trials in the mdx mouse: assessment of reliable and sensitive outcome measures","volume":"39","author":"CF Spurney","year":"2009","journal-title":"Muscle Nerve"},{"issue":"1","key":"pone.0310551.ref017","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.nmd.2011.08.001","article-title":"Endpoint measures in the mdx mouse relevant for muscular dystrophy pre-clinical studies","volume":"22","author":"YM Kobayashi","year":"2012","journal-title":"Neuromuscul Disord"},{"issue":"9","key":"pone.0310551.ref018","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1016\/j.ajpath.2017.05.010","article-title":"Magnetic Resonance Monitoring of Disease Progression in mdx Mice on Different Genetic Backgrounds","volume":"187","author":"R Vohra","year":"2017","journal-title":"Am J Pathol"},{"key":"pone.0310551.ref019","article-title":"MR imaging of the mouse hindlimb musculature (T2 weighted and T2 map): protocols.io; 2023.","author":"EA Waters"},{"key":"pone.0310551.ref020","unstructured":"Image Segmentation Evaluation Using Standard Metrics (Python): Thermo Fisher Scientific; 2021 [updated March 8, 2021; cited 2023 May 1, 2023]. Available from: https:\/\/xtras.amira-avizo.com\/xtras\/image-segmentation-evaluation-using-standard-metrics-python."},{"key":"pone.0310551.ref021","article-title":"Pearson Mode Skewness MathWorld\u2014A Wolfram Web Resource: Mathworld","author":"EW Weisstein","year":"2023"},{"issue":"12","key":"pone.0310551.ref022","doi-asserted-by":"crossref","first-page":"3703","DOI":"10.1172\/JCI39845","article-title":"Latent TGF-beta-binding protein 4 modifies muscular dystrophy in mice","volume":"119","author":"A Heydemann","year":"2009","journal-title":"J Clin Invest"},{"issue":"2","key":"pone.0310551.ref023","doi-asserted-by":"crossref","DOI":"10.1242\/dmm.040832","article-title":"A gene-edited mouse model of limb-girdle muscular dystrophy 2C for testing exon skipping.","volume":"13","author":"AR Demonbreun","year":"2019","journal-title":"Dis Model Mech."},{"issue":"11","key":"pone.0310551.ref024","doi-asserted-by":"crossref","first-page":"4657","DOI":"10.1172\/JCI128840","article-title":"Recombinant annexin A6 promotes membrane repair and protects against muscle injury","volume":"129","author":"AR Demonbreun","year":"2019","journal-title":"J Clin Invest"},{"issue":"3","key":"pone.0310551.ref025","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/s41592-019-0686-2","article-title":"SciPy 1.0: fundamental algorithms for scientific computing","volume":"17","author":"P Virtanen","year":"2020","journal-title":"Python. Nature Methods"},{"issue":"85","key":"pone.0310551.ref026","first-page":"2825","article-title":"Scikit-learn: Machine Learning in Python","volume":"12","author":"F Pedregosa","year":"2011","journal-title":"Journal of Machine Learning Research"},{"key":"pone.0310551.ref027","doi-asserted-by":"crossref","unstructured":"McKinney W. Data Structures for Statistical Computing in Python. In: van der Walt S, Millman J, editors. Proceedings of the 9th Python in Science Conference; 20102010. p. 56\u201361.","DOI":"10.25080\/Majora-92bf1922-00a"},{"issue":"3","key":"pone.0310551.ref028","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1109\/MCSE.2007.55","article-title":"Matplotlib: A 2D Graphics Environment","volume":"9","author":"JD Hunter","year":"2007","journal-title":"Computing in Science & Engineering"},{"issue":"7825","key":"pone.0310551.ref029","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/s41586-020-2649-2","article-title":"Array programming with NumPy","volume":"585","author":"CR Harris","year":"2020","journal-title":"Nature"},{"issue":"2","key":"pone.0310551.ref030","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1177\/096228029900800204","article-title":"Measuring agreement in method comparison studies.","volume":"8","author":"JM Bland","year":"1999","journal-title":"Statistical Methods in Medical Research"},{"key":"pone.0310551.ref031","volume-title":"Waters Demonbreun MDX MRI Manuscript Data Package.","author":"EA Waters","year":"2023"},{"issue":"6","key":"pone.0310551.ref032","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1002\/mrm.20721","article-title":"Noninvasive monitoring of gene correction in dystrophic muscle","volume":"54","author":"G Walter","year":"2005","journal-title":"Magnetic Resonance in Medicine"},{"issue":"6","key":"pone.0310551.ref033","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1002\/mus.21986","article-title":"Changes in muscle T2 and tissue damage after downhill running in mdx Mice","volume":"43","author":"S Mathur","year":"2011","journal-title":"Muscle & Nerve"},{"issue":"10","key":"pone.0310551.ref034","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1002\/(SICI)1097-4598(199910)22:10<1367::AID-MUS5>3.0.CO;2-H","article-title":"Quantitative magnetic resonance imaging of the mdx mouse model of Duchenne muscular dystrophy","volume":"22","author":"JF Dunn","year":"1999","journal-title":"Muscle Nerve"},{"key":"pone.0310551.ref035","article-title":"Technical Note: Extension of CERR for computational radiomics: A comprehensive MATLAB platform for reproducible radiomics research.","author":"AP Apte","year":"2018","journal-title":"Med Phys"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0310551","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T17:41:58Z","timestamp":1726767718000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0310551"}},"subtitle":[],"editor":[{"given":"Nirakar","family":"Sahoo","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2024,9,19]]},"references-count":35,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,9,19]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0310551","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,19]]}}}