{"id":{"repo_id":"columbia-diss","oai_identifier":"oai:academiccommons.columbia.edu:10.7916/D89W0NGX"},"canonical_url":"https://search.dev.ndltd.org/etd/columbia-diss/oai:academiccommons.columbia.edu:10.7916/D89W0NGX","repository":{"repo_id":"columbia-diss","name":"Columbia University","base_url":"https://academiccommons.columbia.edu/oai"},"display":{"title":"The Limb-Leaf Design: A New Way to Explore the Dose Response Curve in Adaptive Seamless Phase II/III Trials","abstract":"This dissertation proposes a method to explore a dose response curve adaptively, allowing new doses to be inserted into the trial after initial results have been observed. The context of our work is adaptive seamless Phase II/III trials and a systematic Limb-Leaf Design is developed. In a case of a nonmonotonic dose response curve where the desired level of effect exists in only a narrow dose range, a simulated comparison between a Limb-Leaf Design and a standard (Thall, Simon, and Ellenberg or TSE-type) adaptive seamless design shows a savings in risk adjusted expected sample size of up to 25%. Chapter 1 is a review of concepts and particular adaptive seamless designs of interest. Chapter 2 proposes dose addition in adaptive seamless designs and identifes ALS research as an area of application. Chapter 3 develops dose addition as an application of existing methodology. Chapter 4 identifies shortcomings of this approach and proposes a new Horizontal Test as the basis for the Limb-Leaf Design. Chapter 5 supports the development of the Limb-Leaf Design with several theoretical observations. The Limb-Leaf Design is developed in Chapters 6 and 7. Chapter 8 shows a comparison of the Limb-Leaf Design with a TSE-type adaptive seamless design by simulation. Future work is suggested in Chapter 9.","abstract_html":"This dissertation proposes a method to explore a dose response curve adaptively, allowing new doses to be inserted into the trial after initial results have been observed. The context of our work is adaptive seamless Phase II/III trials and a systematic Limb-Leaf Design is developed. In a case of a nonmonotonic dose response curve where the desired level of effect exists in only a narrow dose range, a simulated comparison between a Limb-Leaf Design and a standard (Thall, Simon, and Ellenberg or TSE-type) adaptive seamless design shows a savings in risk adjusted expected sample size of up to 25%. Chapter 1 is a review of concepts and particular adaptive seamless designs of interest. Chapter 2 proposes dose addition in adaptive seamless designs and identifes ALS research as an area of application. Chapter 3 develops dose addition as an application of existing methodology. Chapter 4 identifies shortcomings of this approach and proposes a new Horizontal Test as the basis for the Limb-Leaf Design. Chapter 5 supports the development of the Limb-Leaf Design with several theoretical observations. The Limb-Leaf Design is developed in Chapters 6 and 7. Chapter 8 shows a comparison of the Limb-Leaf Design with a TSE-type adaptive seamless design by simulation. Future work is suggested in Chapter 9.","abstract_has_math":false,"creators":["Spivack, John Henry"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2011,"date_issued":"2011","date_published":"2011","updated_at":"2026-07-24T01:44:16Z","subjects":["Biometry","Clinical trials--Design","Amyotrophic lateral sclerosis"],"languages":["English"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.7916/D89W0NGX","outbound_label":"DOI","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Spivack, John Henry"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2011"]},{"key":"dc:type","label":"Dc Type","values":["Theses"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Biometry","Clinical trials--Design","Amyotrophic lateral sclerosis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["English"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://doi.org/10.7916/D89W0NGX"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["This dissertation proposes a method to explore a dose response curve adaptively, allowing new doses to be inserted into the trial after initial results have been observed. The context of our work is adaptive seamless Phase II/III trials and a systematic Limb-Leaf Design is developed. In a case of a nonmonotonic dose response curve where the desired level of effect exists in only a narrow dose range, a simulated comparison between a Limb-Leaf Design and a standard (Thall, Simon, and Ellenberg or TSE-type) adaptive seamless design shows a savings in risk adjusted expected sample size of up to 25%. Chapter 1 is a review of concepts and particular adaptive seamless designs of interest. Chapter 2 proposes dose addition in adaptive seamless designs and identifes ALS research as an area of application. Chapter 3 develops dose addition as an application of existing methodology. Chapter 4 identifies shortcomings of this approach and proposes a new Horizontal Test as the basis for the Limb-Leaf Design. Chapter 5 supports the development of the Limb-Leaf Design with several theoretical observations. The Limb-Leaf Design is developed in Chapters 6 and 7. Chapter 8 shows a comparison of the Limb-Leaf Design with a TSE-type adaptive seamless design by simulation. Future work is suggested in Chapter 9."]},{"key":"dc:title","label":"Title","values":["The Limb-Leaf Design: A New Way to Explore the Dose Response Curve in Adaptive Seamless Phase II/III Trials"]}]}],"canonical_facts":{"dc:creator":["Spivack, John Henry"],"dc:date":["2011"],"dc:description":["This dissertation proposes a method to explore a dose response curve adaptively, allowing new doses to be inserted into the trial after initial results have been observed. The context of our work is adaptive seamless Phase II/III trials and a systematic Limb-Leaf Design is developed. In a case of a nonmonotonic dose response curve where the desired level of effect exists in only a narrow dose range, a simulated comparison between a Limb-Leaf Design and a standard (Thall, Simon, and Ellenberg or TSE-type) adaptive seamless design shows a savings in risk adjusted expected sample size of up to 25%. Chapter 1 is a review of concepts and particular adaptive seamless designs of interest. Chapter 2 proposes dose addition in adaptive seamless designs and identifes ALS research as an area of application. Chapter 3 develops dose addition as an application of existing methodology. Chapter 4 identifies shortcomings of this approach and proposes a new Horizontal Test as the basis for the Limb-Leaf Design. Chapter 5 supports the development of the Limb-Leaf Design with several theoretical observations. The Limb-Leaf Design is developed in Chapters 6 and 7. Chapter 8 shows a comparison of the Limb-Leaf Design with a TSE-type adaptive seamless design by simulation. Future work is suggested in Chapter 9."],"dc:identifier":["https://doi.org/10.7916/D89W0NGX"],"dc:language":["English"],"dc:subject":["Biometry","Clinical trials--Design","Amyotrophic lateral sclerosis"],"dc:title":["The Limb-Leaf Design: A New Way to Explore the Dose Response Curve in Adaptive Seamless Phase II/III Trials"],"dc:type":["Theses"]},"updated_at":"2026-07-24T01:44:16Z"}