Lessons Learned in Establishing a Clinical Sequencing Lab

In 2009, the Medical College of Wisconsin (MCW; Milwaukee) became one of the first in the nation to utilize whole-genome sequencing (WGS) for clinical, diagnostic purposes in patients unsuccessfully resolving diagnostic odysseys. In an invited commentary published July 17 in Science Translational Medicine, the founders of MCW’s Human and Molecular Genetic Center (HMGC) discuss lessons learned in converting a sequencing laboratory designed for research into a clinical program. They offer guidance regarding the practical, technological, economical, and ethical considerations that other laboratories planning their entry into clinical WGS and whole-exome sequencing must address. The genomics medical clinic successfully sequenced and diagnosed its first patient in 2009 in collaboration with Children’s Hospital of Wisconsin and Froedtert Hospital. However, the seed was planted for opening a clinical sequencing laboratory back in 2004 when Howard Jacob, Ph.D., HMGC’s director, and colleagues undertook a $100 million, two-year project to sequence a rat genome. Noting the significant improvement in sequencing efficiency from the $1 billion, 10-year human genome sequence, Jacob and colleagues thought it would be reasonable to assume that genome sequencing would be in the clinic by 2014, he tells DTTR. “Our clinical program is built around the principal idea that making a diagnosis is essential, even in cases where the results may not lead to better treatment” but can change the management plan for the patient, the authors write. To date MCW’s HMGC has sequenced more than 30 whole genomes and 70 whole exomes, primarily in children, yielding a definitive diagnosis in roughly 27 percent of cases for rare or undiagnosed diseases. The center suspects that in some of the 73 percent of unsolved cases WGS has identified the correct variants but there is currently no evidence in the literature supporting causality or clinical significance. Jacob says that while some definitive lessons have been learned, with each case HMGC continues defining and redefining its program. “Our initial concerns were cost and data accuracy, but the major challenges turned out to be the logistics of delivering genome sequence information to clinicians, how clinicians use the data, and how patients and their families deal with the secondary [incidental] findings,” the authors write in the paper. Jacob adds that while “with each case we have done we have learned something, we hope to get to a point where it is turnkey.” While some have argued for a strategy of outsourcing WGS to expert centers, the authors suggest that WGS will become more widespread in part because of advantages associated with local execution, including speed, compliant data storage, and easier interactions with the clinical team. The initial challenge, they say, will be overcoming clinicians’ perception that WGS is an expensive, nonuseful clinical tool. While recognizing that each integrated genomic medicine clinic will face some institution-specific considerations, the authors cite the following practical considerations for other labs to consider. Legal Compliance. New clinical genomics laboratories need to identify state and local laws and hospital guidelines that affect storage of clinical or laboratory data and samples. Future guidelines are expected to clarify the types of genomic sequence data that need to be disclosed to the patient and stored. (For more information on the returning of incidental findings, please Inside the Diagnostics Industry on page 5.) Workflow. Clinical application of WGS involves multiple personnel, including genetic counselors, clinical geneticists, pathologists, clinical laboratory personnel, bioinformaticians, and the ordering clinician. The founders of HMGC believe the ideal solution develops across departments to integrate all needed personnel and expertise. Analytical Processes. In clinical laboratories, clinical processes must be documented and validated. MCW has required some significant alterations to existing protocols, given that HMGC began as a research laboratory. “In a research lab it is a different mind-set. As part of the research, protocols are modified and evolve as [researchers] discover it is faster to do it one way or another,” Jacob says. “As a clinical lab you must lock down the protocols and there can’t be deviations. There is no difference in the technical abilities of the techs, it is just a different mind-set.” In order to obtain Clinical Laboratory Improvement Amendments certification and College of American Pathologists accreditation, HMGC developed and wrote 1,192 pages of standard operating procedures. HMGC also developed an in-house, tertiary analysis platform called CarpeNovo that is updated and revalidated every six months (a process that takes four weeks to six weeks). Clinician Education. Successful implementation is dependent upon clinicians seeing the value in WGS. “We built this clinic with clinicians based on what type of information they needed,” Jacob explains. “To tell them this will change medical practice in 10 years doesn’t help them with the patient they are going to see in 15 minutes.” Integrating Data. Electronic health records are currently not equipped to integrate comprehensive clinical and phenotype patient profiles with the variants discovered in the patient’s genome. To address these needs, MCW created an in-house software (ClinMiner) to integrate data sources and reporting languages. Reimbursement. While the cost of sequencing is expected to further decline, most insurers, including Medicaid, Medicare, and many private payers, will not yet pay for WGS. HMGC says they have had “some success” by demonstrating that the cost of sequencing one whole genome is more economical than ordering multiple genetic tests. “There is a lot of discussion of why it won’t work except for a few diseases and the cost. But the way I see it, it is not if [WGS] will change medicine, it is when. There is value in the genome to you, your family, and to society,” says Jacob. “People get uncomfortable because there are no easy answers—you can’t pull this off the web. Instead of thinking why not to do it, partner with someone. We challenge the fence-sitters to do 20 cases of their own and see whether WGS adds value to clinical decisionmaking. I would be shocked if a laboratory does 20 and doesn’t continue with it.” Takeaway: Whole-genome sequencing will permeate clinical medicine, initially primarily in cases of patients who have unsuccessfully undergone a diagnostic odyssey. While delivering genome sequence data to clinicians remains a challenge requiring institution-specific development of information solutions, the value WGS adds to clinical decisionmaking and an improving economic case will further sway early adopters.