Participants were recruited to the Cardiovascular Health Improvement Project (CHIP), a longitudinal cardiovascular biobank within the Michigan Medicine Frankel Cardiovascular Center, initiated in 2013; biobank recruitment is ongoing [15]. The primary focus is to recruit patients with aortic disease; governance is provided by three executive committees (Additional file 1, Committees). The University of Michigan Institutional Review Board (IRBMED) approved all protocols and procedures (HUM00052866). Eligible participants providing written informed consent between 2012 and 2015 were informed that genetic results may be returned in the future. All aortic cases represented here were enrolled in this manner. In February 2016, the language in the informed consent form was amended and specifically asked participants to opt-in to receive research genetic results for cardiovascular disease and for other diseases (e.g. cancer). After opt-in became available in 2016, 94% of participants (3423/3627) requested to have clinically-actionable variants related to cardiovascular disease returned. For both consent processes described above, participants were informed that the decision to return results would be based on medical expertise and access to sufficient resources (e.g., time and funding). The research was performed in accordance with the Declaration of Helsinki.
Whole exome sequencing and variant annotation
Whole exome sequencing was performed on a subset of biobank participants, including 240 patients with thoracic aortic dissection or rupture and 258 controls matched for age, sex, and ancestry with no cardiovascular conditions from the Michigan Genomics Initiative. Detailed methods on sequencing, variant calling, and quality control has been previously published [13]. In brief, an external laboratory blinded to case–control status, identified variants in 11 genes (COL3A1, FBN1, SMAD3, TGFB2, TGFBR1, TGFBR2, ACTA2, MYH11, MYLK, LOX, PRKG1), which were annotated and categorized as pathogenic, of unknown significance, or benign for aortic dissection according to the American College of Medical Genetics (ACMG) criteria [12, 13, 16]. Findings pertaining to patient demographics, clinical characteristics, risks factors and surgical outcomes have been previously published [13, 17].
Operational steps for recontact and disclosure
Additional file 1: Table S1 summarizes how decisions were made and by whom, which led to the operational steps implemented for recontact and disclosure of the pathogenic variants identified in 26 individuals (Figs. 1, 2). In brief, the principal investigator summarized the de-identified pathogenic variant results to medical and genetic experts (e.g., surgeons and the CHIP Medical Findings and Steering Committees, Additional file 1: Material 1). It was unanimously agreed upon that participants should be recontacted as clinical care for themselves and/or at-risk family members (i.e., surveillance, surgical management) would change based on having a pathogenic variant [14]. Next, to confirm the presence of pathogenic variants, a new DNA sample was extracted from a stored biospecimen (a different biospecimen from the same participant), and targeted sequencing using molecular inversion probes (MIPs) methodology was used and 100% pathogenic variant replication was observed [13].
We opted to initiate recontact via US certified mail based on survey results from 250 participants enrolled in CHIP biobank wherein 94% indicated their preference to receive clinically actionable aortic results [18]. This process provided a guaranteed documentation of letter receipt without disclosing the gene or variant to preserve the participant’s “right not to know” and to opt-in: (1) to learn their research genetic result; and (2) to receive genetic counseling, which would be documented into the Electronic Health Record (EHR).
Prior to mailing letters, the cardiothoracic surgeons overseeing the participants’ clinical care were contacted via email and informed that one of their patients (identity was not disclosed) would be receiving a letter indicating that he/she likely carried an alteration in their DNA that may cause aortic disease. The cardiothoracic surgeons were also informed that genetic counseling and confirmatory genetic testing would be offered at no cost. The purpose of the email was to prepare the cardiothoracic surgeons in the event that their patient(s) would ask about the letter and/or their genetic status (Additional file 1: Material 2, Physician Letter). Next, known living participants were mailed letters (neither the gene nor variant was disclosed), which prompted interested recipients to schedule an appointment with a board certified genetic counselor with cardiovascular genetics expertise (Additional file 1: Material 3, Participant Letter).
Disclosure process
Participants responded to the letter in one of the following ways:
-
1.
They received the letter, made a return phone call to the genetic counselor (or the genetic counselor phoned the participant after a week), and scheduled a genetic counseling appointment with the option to receive confirmatory genetic testing in a CLIA laboratory (paid by the research study). Participants were informed that the clinical genetic counseling visit and confirmatory genetic testing would be documented in EHR. Study participants were informed that the research identified a possible causative variant with the option of CLIA confirmation to validate the finding clinically and make it available for extended family. The benefits and limitations of confirmatory genetic testing were discussed with the participant, as well as the implications of genetic testing and clinical screening for themselves and their families. A detailed 3-generation family history was obtained which could be used to aid potential future cascade testing. Supportive resources both within the healthcare system and through patient support organizations were also discussed with participants. At the end of the genetic counseling visit, participants were invited to participate in a survey study about the recontact and disclosure process. Participant interested in receiving CLIA laboratory genetic testing and participating in the survey study provided separate written informed consent (University of Michigan, IRBMED, HUM00146932).
-
2.
They declined genetic counseling and confirmatory genetic testing in a CLIA laboratory during the phone call with the genetic counselor.
-
3.
They did not respond as they were deceased or lost to follow-up.
Impact of process
Participants’ characteristics, understanding of results, and satisfaction with disclosure process
Demographics and clinical outcomes were collected from EHR. An example of the paper survey is provided (Additional file 1: Material 4). To summarize, socioeconomic characteristics, family health history, and history of genetic counseling and genetic testing were collected via self-report. Participant understanding of their condition, the gene associated with their condition, inheritance pattern, and inheritance risk to siblings and children were assessed via novel questions created by study team members with expertise in genetics, public health, survey development, and cardiogenetics. Participant satisfaction with different elements of the results return process—the letter content, length, comprehensibility, resources provided, and information on family member risk—was assessed using Likert scales (1 = Very Unsatisfied to 5 = Very Satisfied). Participant satisfaction with genetic counseling content and process was assessed by the validated 6-item Genetic Counseling Satisfaction scale (items rated from 1 = Strongly Disagree, to 5 = Strongly Agree) [19]. All survey questions measured at or below the eighth grade level on the Flesch-Kincaid readability scale.
Preferences and Information sharing
Six survey items were developed to assess participant preferences regarding mode of results return (multiple-choice), timing of genetic counseling appointment (multiple-choice), and concerns (open-ended). Information sharing was assessed by asking participants to indicate who they informed from a list of family members and other individuals (e.g. physician).
Psychological impact and decisional satisfaction and regret
We assessed the psychosocial impact of receiving genetic research results using the 12-item ‘Feelings About genomiC Testing Results’ (FACToR) Scale. The validated scale includes four subscales, with scores ranging from 0–12 for negative emotions, 0–16 for positive emotions, 0–8 for uncertainty, and 0–8 on privacy. An overall score is generated from the subscales, with higher scores being indicative of higher psychological impairment (i.e. stress) [20]. A validated 5-item scale assessed participants’ level of regret regarding their decision to learn their genetic research results. Scores range from 0 to 100, with higher scores indicating higher levels of decisional regret [21].
Cost analysis
Targeted sequencing using molecular inversion probes (J. Kitzman Laboratory, University of Michigan) was utilized to validate the pathogenic variants identified by the Northwest Genomic Center. Research coordinator time was tracked for letter preparation/mailing, tracking delivery of letter, and project facilitation (hourly rate of $32.21). Genetic counselor time was tracked for all phone calls and face-to-face time with participants (hourly rate of $37.50). The costs for the room charge for genetic counseling visit, phlebotomy and CLIA laboratory genetic testing, in which the gene was sequenced to validate the research genetic result (Invitae Corporation), were extracted from billing records. Mailing costs were tracked for all letters. We evaluated the total cost of the study and average cost per participant. Separate averages were also calculated for those who pursued genetic counseling and confirmatory genetic testing in a CLIA-laboratory and those who did not. The cost of whole exome sequencing and pathogenic variant annotation were not factored into the cost model as these metrics were a part of the parent research study, which preceded the recontact and disclosure process.
Statistical analysis
Data analysis was restricted solely to descriptive statistics due to the small sample size. Data is presented as mean (± SD) for continuous data, n (%) for categorical data, and range for minimum and maximum response to survey items. When calculating overall scores, missingness was accounted for by averaging by the number of questions answered.