Comparative effectiveness of next generation genomic sequencing for disease diagnosis: Design of a randomized controlled trial in patients with colorectal cancer/polyposis syndromes

Carlos J. Gallego, Caroline S. Bennette, Patrick Heagerty, Bryan Comstock, Martha Horike-Pyne, Fuki Hisama, Laura M. Amendola, Robin L. Bennett, Michael O. Dorschner, Peter Tarczy-Hornoch, William M. Grady, S. Malia Fullerton, Susan B. Trinidad, Dean A. Regier, Deborah A. Nickerson, Wylie Burke, Donald L. Patrick, Gail P. Jarvik, David L. Veenstra

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 12months 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 identify useful outcome measures and strategies to address comparative effectiveness questions about the clinical implementation of genomic sequencing in clinical care.