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Identifying optimal study designs that achieve sufficient power for drawing proper statistical inferences to detect group level effects with small sample sizes has been challenging. Moreover, average effects derived from traditional group\u2010level inference do not necessarily apply to individual participants. Here, we introduce\n                    <jats:italic>N<\/jats:italic>\n                    \u2010of\u20101 trials as an innovative study design that can be used to draw valid statistical inference about the effects of interventions on individual participants and can be aggregated across multiple study participants to provide population\u2010level inferences more efficiently than standard group randomized trials.\n                    <jats:italic>N<\/jats:italic>\n                    \u2010of\u20101 trials have been used in healthcare settings since the late 1980s, but without large\u2010scale adoption and with few applications in experimental physiology research settings. In this paper, we introduce the key components and design features of\n                    <jats:italic>N<\/jats:italic>\n                    \u2010of\u20101 trials, describe statistical analysis and interpretations of the results, and describe some available digital tools to facilitate their use using examples from experimental physiology.\n                  <\/jats:p>","DOI":"10.1113\/ep092753","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T09:41:44Z","timestamp":1781862104000},"page":"3525-3545","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Digital\n                    <i>N<\/i>\n                    \u2010of\u20101 trials and their application in experimental physiology"],"prefix":"10.1113","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9966-6819","authenticated-orcid":false,"given":"Stefan","family":"Konigorski","sequence":"first","affiliation":[{"name":"Hasso Plattner Institute for Digital Engineering  Potsdam Germany"},{"name":"Digital Engineering Faculty University of Potsdam  Potsdam Germany"},{"name":"Hasso Plattner Institute for Digital Health at Mount Sinai Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"German Institute of Human Nutrition Potsdam\u2010Rehbruecke Department of Computational Precision Nutrition Nuthetal  Germany"},{"name":"German Center for Diabetes Research (DZD), M\u00fcnchen\u2010Neuherberg  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Ried\u2010Larsen","sequence":"additional","affiliation":[{"name":"The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Rigshospitalet University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0855-5313","authenticated-orcid":false,"given":"Christopher H.","family":"Schmid","sequence":"additional","affiliation":[{"name":"Department of Biostatistics School of Public Health Brown University  Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0167167"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.010775"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1113\/EP087712"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13063-015-0590-8"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1113\/EP091560"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00421-019-04078-w"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jrsm.12"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.28.1.108"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.00632"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-29854-2"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1201\/b10905"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmpt.2020.09.005"},{"key":"e_1_2_10_14_1","volume-title":"Planning of experiments","author":"Cox D. 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