Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot

Abstract

While consensus regarding the return of secondary genomic findings in the clinical setting has been reached, debate about such findings in the research setting remains. We developed a hybrid, research-clinical translational genomics process for research exome data coupled with a CLIA-validated secondary findings analysis. Eleven intramural investigators from ten institutes at the National Institutes of Health piloted this process. Nearly 1,200 individuals were sequenced and 14 secondary findings were identified in 18 participants. Positive secondary findings were returned by a genetic counselor following a standardized protocol, including referrals for specialty follow-up care for the secondary finding local to the participants. Interviews were undertaken with 13 participants 4 months after receipt of a positive report. These participants reported minimal psychologic distress within a process to assimilate their results. Of the 13, 9 reported accessing the recommended health care services. A sample of 107 participants who received a negative findings report were surveyed 4 months after receiving it. They demonstrated good understanding of the negative secondary findings result and most expressed reassurance (64%) from that report. However, a notable minority (up to 17%) expressed confusion regarding the distinction of primary from secondary findings. This pilot shows it is feasible to couple CLIA-compliant secondary findings to research sequencing with minimal harms. Participants managed the surprise of a secondary finding with most following recommended follow up, yet some with negative findings conflated secondary and primary findings. Additional work is needed to understand barriers to follow-up care and help participants distinguish secondary from primary findings.

Patient‐centered care and genomic medicine: A qualitative provider study in the military health system

“…This suggests either a lack of processes and procedures within the DoD for care of at‐risk individuals with secondary findings, or a lack of awareness or experience with established pathways. Some results suggest that returning secondary findings to patients and participants can positively impact medical management and carry minimal psychological effects (Sapp et al, ). However, these types of outcomes were achieved in settings with robust infrastructure to allow for informed consent, expert interpretation, and post‐test genetic counseling.…”

Secondary findings: How did we get here, and where are we going?

“…First, while some initial studies showed higher rates of SF discovery, perhaps due to variant misclassification and application of the recommendations among selected populations, most empiric studies and modeling have generally supported the original estimate (Johnston et al, 2012) that 1%-2% of unselected populations have a SF on the ACMG list (Amendola et al, 2015;Cassa, Tong, & Jordan, 2013;Ding, Burnett, & Chesher, 2015;Dorschner et al, 2013;Natarajan et al, 2016;Olfson et al, 2015;Sapp et al, 2018;Xue et al, 2012;Yang et al, 2014). However, early research suggests a high percentage of unselected individuals found to carry one of the ACMG SF gene variants appear not to have a family history that would warrant referral for genetic evaluation (e.g., Sapp et al, 2018). This issue, which was raised both by the original recommendation paper and by some of the early commentary papers (Burke et al, 2013), suggests that current penetrance data may overestimate the true magnitude of lifetime risks for pathogenic variants in these genes, particularly in families without a history of affected individuals.…”

“…For example, some cancer patients report a wish to focus on primary findings (Kaphingst et al, 2016), whereas other research has shown that a majority of cancer patients undergoing tumor profiling want disclosure of incidental findings related to both actionable and non-actionable conditions (Yushak et al, 2016). After receiving results, early research data suggest that even if patients have a short-term psychological response, they do not have significant regret, at least in the short term (Sapp et al, 2018); this mirrors what has been seen for other adult onset predictive genetic testing. Patients have also indicated a preference for the term "additional findings" over either "incidental" or "secondary," as "additional" is perceived as a more neutral and understandable term (Tan et al, 2017).…”

Favoriser l'autonomie du patient face aux données additionnelles en médecine génomique

“…Nous entendons par données « fiables » l'identification de variants pathogènes ou probablement pathogènes, respectivement de classe 5 ou 4 selon la classification de l'ACMG [30] dans des gènes bien connus en pathologie, pour lesquels une corrélation génotype-phénotype est clairement établie avec un haut degré d'actionnabilité pour le patient et sa famille. [15]. Les patients sont également influencés par la confiance qu'ils ont dans leur médecin qui leur fait signer le consentement et par le manque de recul sur les conséquences que peuvent avoir de telles connaissances sur eux.…”

“…Par exemple, la confiance qu'un patient a envers son médecin peut le conduire à accepter aveuglément ce que celui-ci lui propose : il est rare qu'un patient refuse les examens médicaux qui lui sont proposés [14]. Le désir de savoir est aussi nourri par le passif d'errance médicale de beaucoup de patients consultant en génétique et qui peuvent alors confondre dans leur précipitation donnée primaire et données additionnelles [15]. Est-ce le désir de savoir, un désir ici irréfléchi et incontrôlé, qui détermine la décision du patient?…”