1f4eb6d4a2d3afa3ac02123c55c72a10 277654.pdf 735321e1951492bcf81c36dab9fbeec50fd61b98 277654.pdf 55a2894ffae3f24afa27155a61c5e3d19ed4ba6bc5ef0f4fcc09132117d43a27 277654.pdf Title: Using Interpretable Machine Learning to Identify Baseline Predictive Factors of Remission and Drug Durability in Crohn’s Disease Patients on Ustekinumab Subject: Ustekinumab has shown efficacy in Crohn’s Disease (CD) patients. To identify patient profiles of those who benefit the most from this treatment would help to position this drug in the therapeutic paradigm of CD and generate hypotheses for future trials. The objective of this analysis was to determine whether baseline patient characteristics are predictive of remission and the drug durability of ustekinumab, and whether its positioning with respect to prior use of biologics has a significant effect after correcting for disease severity and phenotype at baseline using interpretable machine learning. Patients’ data from SUSTAIN, a retrospective multicenter single-arm cohort study, were used. Disease phenotype, baseline laboratory data, and prior treatment characteristics were documented. Clinical remission was defined as the Harvey Bradshaw Index 4 and was tracked longitudinally. Drug durability was defined as the time until a patient discontinued treatment. A total of 439 participants from 60 centers were included and a total of 20 baseline covariates considered. Less exposure to previous biologics had a positive effect on remission, even after controlling for baseline disease severity using a non-linear, additive, multivariable model. Additionally, age, body mass index, and fecal calprotectin at baseline were found to be statistically significant as independent negative risk factors for both remission and drug survival, with further risk factors identified for remission. Keywords: Crohn’s Disease; ustekinumab; predictive factors Author: María Chaparro, Iria Baston-Rey, Estela Fernández Salgado, Javier González García, Laura Ramos, María Teresa Diz-Lois Palomares, Federico Argüelles-Arias, Eva Iglesias Flores, Mercedes Cabello, Saioa Rubio Iturria, Andrea Núñez Ortiz, Mara Charro, Daniel Ginard, Carmen Dueñas Sadornil, Olga Merino Ochoa, David Busquets, Eduardo Iyo, Ana Gutiérrez Casbas, Patricia Ramírez de la Piscina, Marta Maia Boscá-Watts, Maite Arroyo, María José García, Esther Hinojosa, Jordi Gordillo, Pilar Martínez Montiel, Benito Velayos Jiménez, Cristina Quílez Ivorra, Juan María Vázquez Morón, José María Huguet, Yago González-Lama, Ana Isabel Muñagorri Santos, Víctor Manuel Amo, María Dolores Martín Arranz, Fernando Bermejo, Jesús Martínez Cadilla, Cristina Rubín de Célix, Paola Fradejas Salazar, Antonio López San Román, Nuria Jiménez, Santiago García-López, Anna Figuerola, Itxaso Jiménez, Francisco José Martínez Cerezo, Carlos Taxonera, Pilar Varela, Ruth de Francisco, David Monfort, Gema Molina Arriero, Alejandro Hernández-Camba, Francisco Javier García Alonso, Manuel Van Domselaar, Ramón Pajares-Villarroya, Alejandro Núñez, Francisco Rodríguez Moranta, Ignacio Marín-Jiménez, Virginia Robles Alonso, María del Mar Martín Rodríguez, Patricia Camo-Monterde, Iván García Tercero, Mercedes Navarro-Llavat, Lara Arias García, Daniel Hervías Cruz, Sebastian Kloss, Alun Passey, Cynthia Novella, Eugenia Vispo, Manuel Barreiro-de Acosta and Javier P. Gisbert Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Aug 10 10:33:55 2022 CEST ModDate: Wed Aug 10 10:43:45 2022 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 17 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1542141 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- DGBDNV+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 YFNERV+VnURWPalladioL Type 1 Custom yes yes no 15 0 OQTKOJ+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 CWVNYY+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 VBTYRF+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 XPUSBJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 46 0 BSDWLC+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 49 0 VBAQIR+CMSY10 Type 1 Builtin yes yes no 71 0 CKBPVA+EURM10 Type 1 Builtin yes yes no 78 0 GJMNKI+PalatinoLinotype,Bold 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277654.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-07-13 09:28:37 CEST Size: 1542141 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 307 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Children: Item: Title: Performance of Models Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Significant Variables Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Position of Ustekinumab in the Treatment Journey Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Role of Concomitant Steroids Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Appendix A Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Children: Item: Title: Missing Values Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Drop-Out in Longitudinal Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Shape Constraints Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Interaction Effects Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Info: Title: Using Interpretable Machine Learning to Identify Baseline Predictive Factors of Remission and Drug Durability in Crohn’s Disease Patients on Ustekinumab Author: María Chaparro, Iria Baston-Rey, Estela Fernández Salgado, Javier González García, Laura Ramos, María Teresa Diz-Lois Palomares, Federico Argüelles-Arias, Eva Iglesias Flores, Mercedes Cabello, Saioa Rubio Iturria, Andrea Núñez Ortiz, Mara Charro, Daniel Ginard, Carmen Dueñas Sadornil, Olga Merino Ochoa, David Busquets, Eduardo Iyo, Ana Gutiérrez Casbas, Patricia Ramírez de la Piscina, Marta Maia Boscá-Watts, Maite Arroyo, María José García, Esther Hinojosa, Jordi Gordillo, Pilar Martínez Montiel, Benito Velayos Jiménez, Cristina Quílez Ivorra, Juan María Vázquez Morón, José María Huguet, Yago González-Lama, Ana Isabel Muñagorri Santos, Víctor Manuel Amo, María Dolores Martín Arranz, Fernando Bermejo, Jesús Martínez Cadilla, Cristina Rubín de Célix, Paola Fradejas Salazar, Antonio López San Román, Nuria Jiménez, Santiago García-López, Anna Figuerola, Itxaso Jiménez, Francisco José Martínez Cerezo, Carlos Taxonera, Pilar Varela, Ruth de Francisco, David Monfort, Gema Molina Arriero, Alejandro Hernández-Camba, Francisco Javier García Alonso, Manuel Van Domselaar, Ramón Pajares-Villarroya, Alejandro Núñez, Francisco Rodríguez Moranta, Ignacio Marín-Jiménez, Virginia Robles Alonso, María del Mar Martín Rodríguez, Patricia Camo-Monterde, Iván García Tercero, Mercedes Navarro-Llavat, Lara Arias García, Daniel Hervías Cruz, Sebastian Kloss, Alun Passey, Cynthia Novella, Eugenia Vispo, Manuel Barreiro-de Acosta and Javier P. Gisbert Subject: Ustekinumab has shown efficacy in Crohn’s Disease (CD) patients. To identify patient profiles of those who benefit the most from this treatment would help to position this drug in the therapeutic paradigm of CD and generate hypotheses for future trials. The objective of this analysis was to determine whether baseline patient characteristics are predictive of remission and the drug durability of ustekinumab, and whether its positioning with respect to prior use of biologics has a significant effect after correcting for disease severity and phenotype at baseline using interpretable machine learning. Patients’ data from SUSTAIN, a retrospective multicenter single-arm cohort study, were used. Disease phenotype, baseline laboratory data, and prior treatment characteristics were documented. Clinical remission was defined as the Harvey Bradshaw Index 4 and was tracked longitudinally. Drug durability was defined as the time until a patient discontinued treatment. A total of 439 participants from 60 centers were included and a total of 20 baseline covariates considered. Less exposure to previous biologics had a positive effect on remission, even after controlling for baseline disease severity using a non-linear, additive, multivariable model. Additionally, age, body mass index, and fecal calprotectin at baseline were found to be statistically significant as independent negative risk factors for both remission and drug survival, with further risk factors identified for remission. 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