Background: There is growing consensus in favor of returning individual specific research results that are clinically actionable, valid, and reliable. However, deciding what and how research results should be returned remains a considerable challenge. Researchers are key stakeholders in return of results decision-making and implementation. Multi-omics data contains medically relevant findings that could be considered for return. We sought to understand researchers' views regarding the potential for multi-omics data derived return of results from a large, national consortium generating multi-omics data. Methods: Researchers from the Molecular Transducers of Physical Activity Consortium (MoTrPAC) were recruited for in-depth semi-structured interviews. To assess understanding of potential clinical utility for types of data collected and attitudes towards return of results in multi-omic clinical studies, we devised an interview guide focusing on types of results generated in the study which could hypothetically be returned based on review of the literature and professional expertise of team members. The semi-structured interviews were recorded, transcribed verbatim and co-coded. Thematic trends were identified for reporting. Results: We interviewed a total of 16 individuals representative of 11 sites and 6 research roles across MoTrPAC. Many respondents expressed positive attitudes regarding hypothetical multi-omics results return, citing participant rights to their data and perception of minimal harm. Ethical and logistical concerns around the return of multi-omics results were raised, including: uncertain clinical validity, a lack of expertise to communicate results, and an unclear obligation regarding whether to return multi-omics results. Further, researchers called for more guidance from funding agencies and increased researcher education regarding return of results. Conclusion: Overall, researchers expressed positive attitudes toward multi-omic return of results in principle, particularly if medically actionable. However, competing ethical considerations, logistical constraints, and need for more external guidance were raised as key implementation concerns. Future studies should consider views and experiences of other relevant stakeholders, specifically clinical genomics professionals and study participants, regarding the clinical utility of multi-omics information and multi-omics results return.

Kathleen Murphy declares holding Illumina stock. The remaining authors declare no competing interests. Funding This paper was supported in part by the NIH Common Fund (award number U24OD026629).

This paper was supported in part by the NIH Common Fund (award number U24OD026629).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The IRB of Stanford University School of Medicine gave ethical approval for this work (Protocol 57147).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

De-identified transcripts, interview guides and other data are available upon reasonable request to the corresponding author.