Table 3.

Defining and refining a nephrology return of results workflow: key challenges encountered and solutions developed to address them

Protocol and consent amendment
 IRB approval of original biobank study protocol to include return of results mechanismIRB amendment submission to include return of results mechanism in study protocol and recontact option in consent form
Genetic data analysis
 Guidelines needed for:On the basis of a group consensus:
  Genes and/or types of genetic findings discovered in research-setting that classify as “medically relevant” and are appropriate for individual return to participantsDefined “medically relevant” genetic results appropriate for return as diagnostic (primary) or otherwise medically actionable (secondary) findings
Curated a relevant list of 625 genes associated with Mendelian forms of genitourinary disease, to help prioritize variants for analysis for diagnostic (primary) findings
Adopted a priori list of 59 genes deemed medically actionable by the ACMG 
 Prioritization of candidate variants  Developed a bioinformatics pipeline for diagnostic annotation of exome variants
 Obtained subscriptions to proprietary variant databases (e.g., Human Gene Mutation Database) to facilitate variant annotation
  Determination of such variants as suitable for return to nephrology patients Collaborated with a molecular pathologist to review pathogenicity of the findings
 Established quarterly “nephrology genetic sign-out rounds” for interdisciplinary discussions on merits of variants of uncertain significance/candidate variants. Attendance included: molecular pathologists, nephrologists, kidney pathologists, and genetic professionals
 Initiated development of a pipeline to facilitate periodic reanalysis of the sequence data as new genes and variants are identified, and prior genetic findings are reclassified
 Requested additional testing and further follow-up from nephrologists on a case-by-case basis to further inform clinical annotation and appropriateness for return
  Working group to develop and oversee return of results neededCreated multidisciplinary team (nephrologists, research scientists, and a molecular pathologist focused on the development of a return of results workflow
Participant recontact
 Difficulty recontacting participants due to outdated contact informationModified biobank recruitment procedures to include additional contact details (e.g., email, multiple telephone numbers, etc.) at time of enrollment
 Challenges expressed by nephrologists:
  Lack of time to study recontact effortsDesignated a nephrologist associated with the genetic study to liaise between the research team and clinical faculty, to facilitate recontact and return of results
  Uncertainty on recontact procedures for study participants with actionable research-level findings
  Lack of confidence in their ability to counsel patients inquiring about research findingsCollaborated with referring nephrologists to optimize method of recontact
  Concerns regarding potential psychosocial effect and consequences on participants recontacted for return of results
 Concerns expressed by physicians, investigators, and genetics professionalsAdded comprehensive pretest and post-test genetic counseling
Included stakeholders’ viewpoints in the design of the return of results workflow were included
Provided research staff with additional training on consent procedures in order to:
  Difficulty engaging participants to learn more about their genetic findingsEmpower research staff to inform potential participants of the opportunities to learn about “medically relevant” genetic findings identified through the course of research
  Encountered numerous participants requesting disclosure of their preliminary research findings or study results outside the scope of our analyses (e.g., ancestry, etc.) Ensure all potential participants are informed that only clinically-confirmed, actionable genetic findings (e.g., diagnostic and/or secondary findings in the 59 genes recommended for returned by the ACMG), are eligible for return
 Additional training comprised of:
Formal didactic sessions
 Mock recruitment sessions
 Extended observerships with genetic counseling experts
  Long lag times from original enrollment to return of resultsLeveraged opportunities to dual enroll biobank participants in genomic studies where sequencing is performed in a clinically-certified laboratory when possible, which reduced lag time from enrollment to recontact by eliminating need for clinical retesting
 Facilitated communications between genetic analysts and return of results team using a centralized genetic database that alerts the study team of actionable findings, further prioritizing participants for recontact through the eMERGE study
Clinical genetic testing
 Knowledge gaps expressed by physicians:Held educational conferences and didactics on core topics in genomics for the clinical faculty with focus on:
  Difference between clinical- and research-grade genetic testing Fundamental core concepts in genomic medicine
  Interpretation of genetic test reports issued by commercial laboratories Types of data that may be generated in genetic research, including medically actionable findings
 Technical differences between research and clinical laboratories, including federal requirements that only test results generated from a laboratory certified under the CLIA can inform patient care
 Differences among diagnostic sequencing technologies (e.g., targeted sequencing, microarrays, exome sequencing, etc.), including in scope, resolution, analytic sensitivity, along with their respective benefits and limitations (e.g., limitations in detecting for copy number variants and large structural variants with exome sequencing, etc.), and the importance of periodic re-analysis
 Methodology for variant interpretation and clinical annotation 
 Pipeline for clinical confirmation of research-grade genetic findings for our cohort needed Identified CLIA-certified and New York State-approved laboratories to perform confirmatory targeted dideoxy terminator (Sanger) sequencing, with a rapid turn-around time
 Identified additional commercial laboratories that offer alternative methods for validation of research-grade exome data in the event of false negatives with targeted sequencing
 Participants unable to return for clinical re-testing at our center due to relocation to another state Coordinated with the patient’s new primary nephrologist to facilitate referrals to local genetic counselors
Assisted the new primary nephrologists in arranging confirmatory genetic testing
Return of clinically confirmed results and post-test counseling
 Patients express a lack of understanding of the clinical implications of their genetic findings Provided patients with a copy of the return of results consultation note and CLIA-confirmed genetic test report
 Referred patients for additional genetic counseling
 Numerous patients inquire about future pregnancies and family planning options Curated a list of relevant patient support groups and informational websites
 Invited patients and their families to contact the nephrogenetics team with additional questions
Identified maternal–fetal medicine specialists with genetic expertise to refer patients for prenatal and preimplantation genetic diagnostics counseling
 Participants express need for guidance on how best to share the genetic findings with their family membersCreated a family letter template for patients to share with family membersa
Clinical application of findings
 Nephrologists express a need for greater understanding on the next steps in management based on the genetic diagnosis Drafted a detailed nephrogenetics consultation note that includes management recommendations on the basis of the genetic findings (see Section S1 of the Supplemental Material)a
 Met one-on-one with referring nephrologists to discuss the genetic findings and next steps (e.g., referrals, additional testing, etc.) after the return of results visit
 Need for a defined communication pathway for sharing the genetic results and management recommendations with additional providersAddition to electronic health record: Nephrogenetics consultation note
  The CLIA-confirmed genetic test report
  Corresponding ICD-10 code of the genetic diagnosis 
  Communicating with outside providers:
 Invited outside providers to contact us to schedule additional telephone consultations regarding their patient’s genetic findings
 Provided participants with an electronic copy of the nephrogenetics consultation note to share with any additional providers
 Provided local nephrologists with:
  Local nephrologists express need for guidance on next steps in management on the basis of the genetic findings  Telephone consultation to assist in follow-up care for patients no longer followed at our institution
  Outline documenting clinical implications and management recommendations relating to the genetic diagnosis, along with a list of literature references and resources
 Nephrologists express their need for guidance ordering clinical genetic testing, asking: Addition of a genetic counselor for the Division of Nephrology, dedicated to guiding clinicians and patients on various clinical genetic testing options, providing patients with pre-test counseling, and informing clinicians about genetic implications of the findings
  Identified optimal commercial diagnostic laboratories for different indications and provided nephrologists with estimates of the out-of-pocket costs of different genetic tests (e.g., full cost for a clinical exome for a proband and trio; list prices for targeted cystic kidney disease panels offered by different commercial laboratories, etc.), and a list of laboratories offering financial counseling and prior-authorization services, to guide their selection of the most appropriate clinical genetic test
  What genes to assess?  Created nephrology-specific templates for Letter of Medical Necessity for nephrologists to submit to insurance companies when ordering clinical genetic testing, in order to facilitate their requests for prior-authorizations by third-party payers 
  What test to order?   
  What commercial laboratory to choose?   Established a weekly Nephrology Genetics clinic based on the return of results workflow for the evaluation and management of adult nephrology patients with a suspected hereditary nephropathy or a new genetic diagnosis
 Need for a referring mechanism for participants requiring subsequent care based on primary diagnostic findings that implicate additional organ systems and/or with an otherwise medically actionable (secondary) findingCompiled a referral list of subspecialists with genomic expertise in relevant fields
Communicated the genetic findings to identified subspecialists directly before the patient’s scheduled visit (including for ophthalmology, otolaryngology, cardiology, endocrinology, hematology, breast oncology, and maternal–fetal medicine)
  • IRB, Institutional Review Board; ACMG, American College of Medical Genetics and Genomics; eMERGE, Electronic Medical Records and Genomics Network's Phase III Study; CLIA, Clinical Laboratory Improvement Amendments of 1988; ICD-10, The International Statistical Classification of Diseases and Related Health Problems.

  • a An example of the nephrogenetics consultation note and a template of the family letter can be found in Section S1 of the Supplemental Material.