Web Platform vs In-Person Genetic Counselor for Return of Carrier Results From Exome Sequencing: A Randomized Clinical Trial

Abstract

Importance: A critical bottleneck in clinical genomics is the mismatch between large volumes of results and the availability of knowledgeable professionals to return them.

Objective: To test whether a web-based platform is noninferior to a genetic counselor for educating patients about their carrier results from exome sequencing.

Design, setting, and participants: A randomized noninferiority trial conducted in a longitudinal sequencing cohort at the National Institutes of Health from February 5, 2014, to December 16, 2016, was used to compare the web-based platform with a genetic counselor. Among the 571 eligible participants, 1 to 7 heterozygous variants were identified in genes that cause a phenotype that is recessively inherited. Surveys were administered after cohort enrollment, immediately following trial education, and 1 month and 6 months later to primarily healthy postreproductive participants who expressed interest in learning their carrier results. Both intention-to-treat and per-protocol analyses were applied.

Interventions: A web-based platform that integrated education on carrier results with personal test results was designed to directly parallel disclosure education by a genetic counselor. The sessions took a mean (SD) time of 21 (10.6), and 27 (9.3) minutes, respectively.

Main outcomes and measures: The primary outcomes and noninferiority margins (δNI) were knowledge (0 to 8, δNI = -1), test-specific distress (0 to 30, δNI = +1), and decisional conflict (15 to 75, δNI = +6).

Results: After 462 participants (80.9%) provided consent and were randomized, all but 3 participants (n = 459) completed surveys following education and counseling; 398 (86.1%) completed 1-month surveys and 392 (84.8%) completed 6-month surveys. Participants were predominantly well-educated, non-Hispanic white, married parents; mean (SD) age was 63 (63.1) years and 246 (53.6%) were men. The web platform was noninferior to the genetic counselor on outcomes assessed at 1 and 6 months: knowledge (mean group difference, -0.18; lower limit of 97.5% CI, -0.63; δNI = -1), test-specific distress (median group difference, 0; upper limit of 97.5% CI, 0; δNI = +1), and decisional conflict about choosing to learn results (mean group difference, 1.18; upper limit of 97.5% CI, 2.66; δNI = +6). There were no significant differences between the genetic counselors and web-based platform detected between modes of education delivery in disclosure rates to spouses (151 vs 159; relative risk [RR], 1.04; 95% CI, 0.64-1.69; P > .99), children (103 vs 117; RR, 1.07; 95% CI, 0.85-1.36; P = .59), or siblings (91 vs 78; RR, 1.17; 95% CI, 0.94-1.46; P = .18).

Conclusions and relevance: This trial demonstrates noninferiority of web-based return of carrier results among postreproductive, mostly healthy adults. Replication studies among younger and more diverse populations are needed to establish generalizability. Yet return of results via a web-based platform may be sufficient for subsets of test results, reserving genetic counselors for return of results with a greater health threat.

Trial registration: clinicaltrials.gov Identifier: NCT00410241.

Conflict of interest statement

Conflict of Interest Disclosures: Dr L. Biesecker serves as an uncompensated consultant to the Illumina Corp. No other conflicts were reported.

Figures

Figure 1.. Participant Flow

A total of 1001 members of the ClinSeq cohort were assessed for eligibility for this trial. Ultimately, 462 individuals were randomized. NIH CC indicates National Institutes of Health Clinical Center.

Figure 2.. Noninferiority of Trial Outcomes

Mean group differences between educational arms (web-based platform − genetic counselor) noted immediately after (A), 1 month after (B), and 6 months after (C) education with respect to 2 primary outcomes (knowledge, decisional conflict) and 3 secondary outcomes (anxiety, risk worry, risk perception). Test-specific distress is not depicted because a severe floor effect observed at 1 and 6 months rendered parametric tests inappropriate. Noninferiority was tested for outcomes shown with 1-sided 97.5% CIs, and equivalence was tested for the risk perception outcome with a 2-sided 95% CI. The gray shaded portion denotes the noninferiority (or equivalence) range defined by the prespecified margins (δNI or δE), which determines rejection of the null hypothesis if not exceeded. For knowledge, the possible score was 0 to 8 (δNI = −1); anxiety, 6 to 24 (δNI = +2); decisional conflict, 15 to 75 (δNI = +6); risk worry, 1 to 7 (δNI = +1); and risk perception, 1 to 7 (δE = ±1).