{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T18:49:25Z","timestamp":1787856565375,"version":"build-2784847793"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL164906"],"award-info":[{"award-number":["R01HL164906"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Pulmonary arterial hypertension (PAH) clinical trials largely rely on clinically relevant intermediate outcomes, as mortality and lung transplant are infrequent and remote outcomes. The change in 6-minute walk distance (\u03946MWD) is utilized as an intermediate endpoint and is used as a surrogate for clinical worsening events.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We investigate whether the change in 4 composite risk assessment scores\u2014REVEAL Lite 2 (\u0394RL2), European Four Strata (\u0394E4), European Three Strata (\u0394E3), and French Noninvasive score (\u0394FPHN)\u2014are potentially stronger surrogate endpoints than the single-component \u03946MWD in PAH studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using data from the AMBITION and FREEDOM-EV trials, we estimated the percentage of treatment effect in reducing clinical worsening events within 1\u2009year that is attributed to the change on each of the 5 scores between baseline and 12\u201316\u2009weeks\u2019 follow-up. We conducted bootstrap analysis to provide head-to-head comparisons.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Our analysis shows that all 4 composite scores mediate significantly more of the treatment effect compared to 6MWD (29% for \u0394RL2 and \u0394E4 compared to 19% for \u03946MWD; both P &amp;lt;10\u221215). The drug treatment effect accounted for by all 5 scores increases with intermediate\/high-risk patients, and \u0394RL2 had the highest % mediation (37% for \u0394RL2 vs 28% for \u03946MWD; P &amp;lt; 10\u221215).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>RL2 and E4 were the strongest mediators, with RL2 showing the highest mediation in intermediate\/high-risk patients. Until better surrogates are found that mediate over 50% of the treatment effect, RL2 or E4 may serve as alternatives to the 6MWD as intermediate endpoints.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ajrccm\/aamaf003","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T09:04:19Z","timestamp":1769159059000},"page":"616-624","source":"Crossref","is-referenced-by-count":3,"title":["Study of risk assessment scores as surrogate endpoints in pulmonary arterial hypertension trials"],"prefix":"10.1093","volume":"212","author":[{"given":"Yongqi","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Statistics, The Ohio State University , Columbus, OH,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1399-5206","authenticated-orcid":false,"given":"R James","family":"White","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical 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