Participant preferences for the return of non-genetic research results: An interview study of participants from a rheumatoid arthritis trial

Introduction

There are many unanswered questions regarding the return of research results derived from biospecimens (Wong et al., 2018). While there is a large focus on return of research results in genetics, there is limited information available regarding return of research results for non-genetic data generated from biospecimens, and to our knowledge, no such information is available in rheumatology. Non-genetic results include individual-level data unrelated to genomic sequencing, which can include biomarkers, imaging, physiological measures, or behavioral assessments (Botkin et al., 2018; National Heart, Lung, and Blood Institute (NHLBI) Working Group, 2005; National Human Genome Research Institute, 2023). Specifically, non-genetic results derived from biospecimens can include biomarker levels (e.g. proteins, hormones), metabolic profiles, environmental toxin exposures, immunologic markers, and tissue-based histological findings, all of which may hold personal or health relevance for participants despite lacking genomic content.

There have been multiple studies investigating participant preferences regarding the return of individual genetic research results (Bollinger et al., 2012, 2014; Murphy et al., 2008), and some evidence for patient experience, attitudes, and beliefs on genetic versus non-genetic medical conditions (Kass et al., 2007; Plantinga et al., 2003). Genetic information is generally considered differently than non-genetic information on the policy, research, and individual levels, so we cannot assume that public preferences for return of genetic research results would apply for non-genetic research results from biospecimens (Bollinger et al., 2014). Genetic and non-genetic results with unclear clinical benefit present ethical challenges around return. While lacking immediate clinical utility, such findings may still hold personal value for participants. Genetic results, such as variants of uncertain significance, often carry implications for familial risk and identity, warranting stricter regulatory oversight and the need for genetic counseling. In contrast, non-genetic findings, such as exploratory biomarkers, are typically less regulated and may be more variable in interpretation. These differences highlight the need for return-of-results frameworks that are tailored to the type of data and the informational needs of participants, not just clinical actionability.

Less is known about participant preferences, attitudes, and beliefs regarding the return of individual non-genetic research results from biospecimens that are acquired via innovative tests that provide unclear clinical benefit. New tests and technologies can produce results of unclear significance that are not obviously clinically actionable. What is considered clinically actionable information can be less apparent with rheumatologic diseases; rheumatology encompasses both common and esoteric diseases with heterogeneous clinical presentations, making the data associated with these conditions sometimes difficult to interpret.

The Rheumatoid Arthritis Study of the Myocardium (RHYTHM) trial provides an opportunity to (1) gather participant preferences regarding return of individual non-genetic research results from biospecimens involving innovative tests that provide unclear clinical benefit and (2) determine if participants’ attitudes and beliefs about return of individual genetic research results vary from their attitudes and beliefs about return of individual non-genetic research results.

Materials and methods

Results

Characteristics of participants

Participants’ characteristics are shown in Table 1; the mean age was 53 (SD = 9.9, range 34–70) and they were mostly female (88%) and White (47%). The study population also included participants who self-identified as Black (23.5%), Hispanic (23.5%), or other (6%). Interviews lasted about 5 to 25 minutes with an average duration of 12 minutes and 46 seconds.

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Table 1.

Baseline characteristics of participants.

Participant ID(n = 17)	Interview length (min:sec)	Age (years)	Gender	Race/ethnicity
024103	14:24	53	Female	White
044103	06:16	64	Female	Hispanic
047001	11:51	48	Female	Other
070002	10:39	61	Female	White
084016	04:48	48	Male	White
086010	19:13	59	Male	White
092001	15:25	39	Female	Hispanic
100005	11:46	61	Female	Black
101001	24:29	52	Female	White
102009	07:57	57	Female	White
106011	13:35	67	Female	White
122005	12:58	45	Female	Black
143020	09:45	43	Female	Hispanic
147020	08:37	58	Female	Black
154009	16:18	51	Female	Hispanic
166003	13:37	70	Female	White
171034	15:25	34	Female	Black

Discussion

With the evolving advancements in healthcare, we must consider new ethical paradigms that will ensure ethical research. There is a clear ethical motive to notify participants of individual research results that are clinically relevant and/or actionable (Edwards et al., 2012; Klitzman et al., 2013; Ramoni et al., 2013). Consensus groups have also determined that medical actionability should be used to decide if a researcher should return results to a participant (National Bioethics Advisory Commission, 1999). However, new tests and technologies can produce results of unclear significance that are not obviously clinically actionable.

It has become increasingly important to consider a research participant’s preference to receive individual research results and cultivating understanding of those results (Botkin et al., 2018). Participants have also expressed the desire for a less paternalistic approach, and to be able to make the autonomous choice of receiving their results (Cole et al., 2015). Our participants highlighted the need for choice regarding which results are returned, how, and when, emphasizing the ethical duty to embed preference-sensitive mechanisms within the consent process.

Our study advances the ethical discourse on returning individual research results, focusing on non-genetic, non-clinically actionable findings. Participants expressed a strong interest in accessing these results, motivated by values of autonomy, transparency, and empowerment. These insights underscore the ethical imperative to move beyond clinical utility and to integrate participant experiences and preferences into research practices.

Significant changes in federal regulations have allowed people to have greater access to their test results. Since 2014, the Health Insurance Portability and Accountability Act (HIPAA) privacy rule has granted individuals the right to receive a copy of their test results from HIPAA covered laboratories (HIPPA Administrative Simplification. Regulation Text. 45 CFR Parts 160., 2013). In 2017, revisions to the Common Rule further required researchers to disclose whether they will release clinically relevant results, including individual research results, to participants (Federal Policy for the Protection of Human Subjects, 2017). However, the Clinical Laboratory Improvement Amendments (CLIA) of 1988 prohibit the release of individual research results obtained from non-CLIA certified laboratories (Research Testing and Clinical Laboratory Improvement Amendments of 1988 (CLIA) Regulations, 2014). Researchers may use non-CLIA laboratories to analyze biospecimens using innovative methods. In the RHYTHM study, novel microarrays from a non-CLIA certified lab were used to identify antibodies directed against APCAs, serving as an example regarding this tension between returning research results and regulations.

Regulatory barriers, particularly those related to non-CLIA-certified laboratories, complicate the return of results despite their perceived personal significance. Clinical laboratories are subject to rigorous certification ensuring result accuracy and reliability for medical decision-making, whereas research laboratories often lack comparable oversight, raising concerns about the validity and clinical relevance of their findings. However, research labs are often exploring the initial proof and relevance of molecules to a disease process, so there may be no validation possible.

This distinction creates an ethical tension between honoring participant autonomy and protecting against potential harm from uncertain or non-validated results. To address this, researchers should transparently communicate these limitations during informed consent, provide clear guidance on how to interpret research results, and consider offering confirmatory testing in certified labs when appropriate. Future policy should reconcile these constraints with ethical obligations, especially as research increasingly intersects with clinical care.

Although it has been argued that genetic information is not significantly different from other medical information (Beckwith and Alper, 1998; Gostin and Hodge, 1999), it has generally been treated differently on multiple levels. On a policy level, state laws presume that genetic information requires special protection (Annas, 2001). On a research level, a significant amount of attention has been placed on participant preferences regarding the return of individual genetic information (Bollinger et al., 2012, 2014; Murphy et al., 2008). On an individual level, there has been a strong interest in personal genetic information as evidenced by the popularity of direct-to-consumer testing. Research participants are also highly interested in receiving individual genetic research results (Goodman et al., 2018; Vears et al., 2021). However, while many prefer to receive all genetic results (Bollinger et al., 2014; Hoell et al., 2020), when given a choice, some want only some or none at all (Hoell et al., 2020). Participants also express interest in receiving non-genetic research results (Purvis et al., 2017), but they tend to prefer genetic research results—particularly those related to medication response and disease risk (Wilkins et al., 2019)—over non-genetic findings such as heart imaging (Sayeed et al., 2021). Participants of genomic research can also perceive their genetic data as “riskier” than other types of medical data (Ruiz-Canela et al., 2011).

It has been shown that participants’ perceived value of well understood research results is higher than for results of unknown significance (Angal et al., 2023), and most people prefer receiving well-validated individual genetic research results for serious, actionable diseases (Bollinger et al., 2014), which is consistent with existing recommendations (Bookman et al., 2006; Fabsitz et al., 2010; Jarvik et al., 2014; National Bioethics Advisory Commission, 1999). However, many participants value genetic results with no definite clinical use (Allen et al., 2014; Bollinger et al., 2012; Meulenkamp et al., 2010; Murphy et al., 2008), suggesting that return of results should not be limited to those considered clinically actionable (Yu et al., 2014). Our participants had a strong preference to receive their research results, whether genetic or non-genetic, even if they were of unclear clinical benefit or actionability. However, some participants expressed specific concerns about receiving genetic research results. These included implications for current and future generations, misinterpreting results to assume the worst outcome, privacy and confidentiality, and potential effects on insurance coverage.

The three major factors that would affect our participants’ decision to receive non-genetic research results that do not have clear clinical actionability included: (1) Clinical care considerations (2) Empowerment and (3) Personal preference. Similarly, a prior study found that participant expectations for receiving research results included inspiring a change in behavior to improve one’s health, feeling empowered to do something about the results, and providing recommendations if there was a major issue that needed follow up (Sayeed et al., 2021).

Variability in participant preferences, as demonstrated in our study, supports the belief that researchers should offer to share research findings though different modalities, allowing participants to choose from a list of preferred reporting methods at the time of consent (Purvis et al., 2017). When considering the return of individual genetic results, receiving detailed reports has been considered more valuable than providing staff to discuss results (Bollinger et al., 2014). Our participants also preferred detailed reports for non-genetic research results, specifically to share with their primary care provider or specialists to help them interpret their data, similar to those receiving genetic research results (Allen et al., 2014; Richmond et al., 2024). However, it has been shown that participant satisfaction was highest when research results were communicated though a meeting with a researcher (Long et al., 2016), and many of our participants appreciated having this option.

Participants in our study raised several ethical considerations regarding the return of individual non-genetic, non-clinically actionable research results. These included trust (or distrust) in medicine, a participant’s right to data, a researcher’s obligation to return research results, and giving back to participants. Other participants have expressed that receiving research results is valuable and that such disclosure would enhance their trust in researchers (Wilkins et al., 2019). One could argue that participants have a right to individual research results, even if they are not clinically actionable (Fernandez et al., 2004; Shalowitz and Miller, 2005). Most research participants believe they have a right to their data (Purvis et al., 2017) and that researchers are obligated to return individual research results (Bollinger et al., 2012; Meulenkamp et al., 2010). Sharing such information can foster participant engagement in the research process and, as observed in our study, empower participants to take a more active role in their clinical care. Many individuals feel that receipt of individual research results serves both as an incentive to participate (Goodman et al., 2017) and as a form of compensation (Bollinger et al., 2012).

A precautionary strategy would support the comprehensive disclosure of individual research results, accompanied by suitable protective measures to prevent, reduce or manage potential risks to participants (Resnik, 2011). However, the ethical justifications for a generalized duty to return research results have been questioned, one argument being that not all research results will have implications that are considered “exceptional” (Miller et al., 2008). Rather than returning only actionable results, considering a “return of value” may be another approach, focusing on participants’ perceived value of different types of results and considering what participants find most meaningful and potentially beneficial (Wilkins et al., 2019). The counterargument is that the purpose of research is to provide generalizable knowledge rather than individual benefit. Individuals often assume they will certainly benefit from participating in research, highlighting concerns that returning individual results will trigger the therapeutic misconception (Burke et al., 2014).

Other major considerations in returning non-genetic research results include provoking anxiety, distress, and unnecessary medical workups or treatments; researchers have expressed some of these concerns in returning research findings to participants (Purvis et al., 2020; Shalowitz and Miller, 2008), including incidental findings (Cole et al., 2015; Kang et al., 2024). However, our participants did not emphasize these concerns when receiving non-genetic research results, perhaps because our interviews focused on hypothetical results that did not have definitive clinical actionability. Return of genetic research results also does not seem to be associated with substantial psychological harm (Vears et al., 2021).

Our study has some limitations. Interview studies are susceptible to interviewer and social desirability bias, leading participants to not share their true opinions. Due to technical issues, notes rather than transcripts were used for three interviews, which may have limited the data captured. This could have led to missed divergent insights and a premature conclusion that data saturation was reached. Additionally, while thematic analysis allows for rich interpretation, it is inherently subjective and shaped by researcher perspectives, despite efforts to ensure analytic rigor through collaborative coding and review. As with most interview-based research, our findings may also be influenced by self-selection bias; the answers of those who did not participate may have provided additional and diverging themes. Our sample was predominantly female, reflecting both the higher prevalence of RA in women and the demographics of the RHYTHM study, from which 82% of participants were female (Amigues et al., 2019); women may also have been more comfortable discussing personal views. Compared to the broader RHYTHM cohort, our sample included a higher proportion of White and Black participants, with fewer Hispanic participants. This may have influenced the range of perspectives captured, particularly regarding cultural or community-specific experiences. Our demographic data does not include other factors that might affect preferences and would be important to investigate further; it has been shown that preferences for different types of research results differs between socioeconomic groups (Richmond et al., 2024; Wilkins et al., 2019).

Significance and future directions

Recommendations and regulations require investigators to communicate whether, under what circumstances, and how individual research results, especially from biospecimens, will be offered and returned. Our data show both similar and divergent preferences for receiving genetic versus non-genetic research results that do not have clear clinical actionability. Given the variety of preferences regarding what, when, and how non-genetic research results should be returned, it is important to ascertain participant preferences to build trust and confidence in the research process.

We propose a participant-centered framework for returning individual research results focusing on five key guidelines: (1) proactively assessing and respecting participant preferences throughout the consent process and the study; (2) ensuring transparency about result nature, limitations, and implications; (3) providing meaningful participant choice regarding receiving results; (4) navigating regulatory challenges while advocating for policy reform; and (5) promoting equitable and inclusive processes, particularly for underrepresented or marginalized populations. By centering autonomy, transparency, empowerment, and reciprocity, this approach goes beyond narrow clinical utility paradigms and fosters ethically responsible research that builds trust and engagement.

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