title: Comparative effectiveness of next generation genomic sequencing for disease diagnosis: design of a randomized controlled trial in patients with colorectal cancer/polyposis syndromes.
abstract: Whole exome and whole genome sequencing are applications of next generation sequencing transforming clinical care, but there is little evidence whether these tests improve patient outcomes or if they are cost effective compared to current standard of care. These gaps in knowledge can be addressed by comparative effectiveness and patient-centered outcomes research. We designed a randomized controlled trial that incorporates these research methods to evaluate whole exome sequencing compared to usual care in patients being evaluated for hereditary colorectal cancer and polyposis syndromes. Approximately 220 patients will be randomized and followed for 12 months after return of genomic findings. Patients will receive findings associated with colorectal cancer in a first return of results visit, and findings not associated with colorectal cancer (incidental findings) during a second return of results visit. The primary outcome is efficacy to detect mutations associated with these syndromes; secondary outcomes include psychosocial impact, cost-effectiveness and comparative costs. The secondary outcomes will be obtained via surveys before and after each return visit. The expected challenges in conducting this randomized controlled trial include the relatively low prevalence of genetic disease, difficult interpretation of some genetic variants, and uncertainty about which incidental findings should be returned to patients. The approaches utilized in this study may help guide other investigators in clinical genomics to identify useful outcome measures and strategies to address comparative effectiveness questions about the clinical implementation of genomic sequencing in clinical care.
authors.affiliation: Division of Medical Genetics, University of Washington, 1705 NE Pacific Street, K253, Box 357720, Seattle, WA 98195-7720, United States; Pharmaceutical Outcomes Research and Policy Program, University of Washington, 1959 NE Pacific Street, Health Sciences Building, Room H-375, Box 357630, Seattle, WA 98195-7630, United States. Electronic address: carlosjg@uw.edu.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Gallego
authors.affiliation: Pharmaceutical Outcomes Research and Policy Program, University of Washington, 1959 NE Pacific Street, Health Sciences Building, Room H-375, Box 357630, Seattle, WA 98195-7630, United States. Electronic address: cb11@u.washington.edu.
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Bennette
authors.affiliation: Department of Biostatistics, University of Washington, F-600, Health Sciences Building, Box 357232, Seattle, WA 98195-7232, United States. Electronic address: heagerty@uw.edu.
authors.forename: Patrick
authors.initials: P
authors.lastname: Heagerty
authors.affiliation: Department of Biostatistics, University of Washington, F-600, Health Sciences Building, Box 357232, Seattle, WA 98195-7232, United States. Electronic address: bac4@uw.edu.
authors.forename: Bryan
authors.initials: B
authors.lastname: Comstock
authors.affiliation: Division of Medical Genetics, University of Washington, 1705 NE Pacific Street, K253, Box 357720, Seattle, WA 98195-7720, United States. Electronic address: mjpyne@u.washington.edu.
authors.forename: Martha
authors.initials: M
authors.lastname: Horike-Pyne
authors.affiliation: Division of Medical Genetics, University of Washington, 1705 NE Pacific Street, K253, Box 357720, Seattle, WA 98195-7720, United States. Electronic address: fmh2@uw.edu.
authors.forename: Fuki
authors.initials: F
authors.lastname: Hisama
authors.affiliation: Division of Medical Genetics, University of Washington, 1705 NE Pacific Street, K253, Box 357720, Seattle, WA 98195-7720, United States. Electronic address: lauraa7@uw.edu.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Amendola
authors.affiliation: Division of Medical Genetics, University of Washington, 1705 NE Pacific Street, K253, Box 357720, Seattle, WA 98195-7720, United States. Electronic address: robinb@uw.edu.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Bennett
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, VAPSHCS GRECC S-182, 1660 S. Columbian Way, Seattle, WA 98108, United States. Electronic address: mod@uw.edu.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Dorschner
authors.affiliation: Department of Biomedical Informatics and Medical Education, University of Washington, Box 358047, United States. Electronic address: pth@u.washington.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Tarczy-Hornoch
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Division of Gastroenterology, University of Washington, 1100 Fairview Ave. N., Box 19024, Mailstop D4-100, Seattle, WA 98109, United States. Electronic address: wgrady@fhcrc.org.
authors.forename: William M
authors.initials: WM
authors.lastname: Grady
authors.affiliation: Department of Bioethics and Humanities, University of Washington, 1959 NE Pacific Street, A204 Health Sciences Center, Box 357120, Seattle, WA 98195, United States. Electronic address: smfllrtn@u.washington.edu.
authors.forename: S Malia
authors.initials: SM
authors.lastname: Fullerton
authors.affiliation: Department of Bioethics and Humanities, University of Washington, 1959 NE Pacific Street, A204 Health Sciences Center, Box 357120, Seattle, WA 98195, United States. Electronic address: sbtrini@uw.edu.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Trinidad
authors.affiliation: Canadian Centre for Applied Research in Cancer Control, BC Cancer Agency, 2nd Floor, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada. Electronic address: dregier@bccrc.ca.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Regier
authors.affiliation: Department of Genome Sciences, University of Washington, 3720 15th Avenue NE, Foege Building S-250, Box 355065, Seattle, WA 98195, United States. Electronic address: debnick@u.washington.edu.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Bioethics and Humanities, University of Washington, 1959 NE Pacific Street, A204 Health Sciences Center, Box 357120, Seattle, WA 98195, United States. Electronic address: wburke@u.washington.edu.
authors.forename: Wylie
authors.initials: W
authors.lastname: Burke
authors.affiliation: Department of Health Services, University of Washington, Seattle, 4333 Brooklyn Ave NE, Rm 14-101, Box 359455, Seattle, WA 98195-9455, United States. Electronic address: donald@u.washington.edu.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Patrick
authors.affiliation: Division of Medical Genetics, University of Washington, 1705 NE Pacific Street, K253, Box 357720, Seattle, WA 98195-7720, United States. Electronic address: pair@uw.edu.
authors.forename: Gail P
authors.initials: GP
authors.lastname: Jarvik
authors.affiliation: Pharmaceutical Outcomes Research and Policy Program, University of Washington, 1959 NE Pacific Street, Health Sciences Building, Room H-375, Box 357630, Seattle, WA 98195-7630, United States. Electronic address: veenstra@uw.edu.
authors.forename: David L
authors.initials: DL
authors.lastname: Veenstra
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000175:diagnosis / Q000235:genetics; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000523:psychology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics; D057186:Comparative Effectiveness Research; D003362:Cost-Benefit Analysis; D059472:Exome; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing / Q000191:economics / Q000379:methods; D006801:Humans; D057285:Precision Medicine; D012107:Research Design; D017422:Sequence Analysis, DNA / Q000191:economics / Q000379:methods
keywords: Comparative effectiveness research; Genomics; Next generation sequencing; Outcomes research; Randomized clinical trial; Whole exome sequencing