key: cord-0019479-pz3xt6lw
authors: Sayeed, Sabina; Califf, Robert; Green, Robert; Wong, Celeste; Mahaffey, Kenneth; Gambhir, Sanjiv Sam; Mega, Jessica; Patrick-Lake, Bray; Frazier, Kaylyn; Pignone, Michael; Hernandez, Adrian; Shah, Svati H.; Fan, Alice C.; Krüg, Sarah; Shaack, Terry; Shore, Scarlet; Spielman, Susie; Eckstrand, Julie; Wong, Charlene A.
title: Return of individual research results: What do participants prefer and expect?
date: 2021-07-29
journal: PLoS One
DOI: 10.1371/journal.pone.0254153
sha: 2713e6f95eee6c841e46706eba11d15ee93506b7
doc_id: 19479
cord_uid: pz3xt6lw

Newer data platforms offer increased opportunity to share multidimensional health data with research participants, but the preferences of participants for which data to receive and how is evolving. Our objective is to describe the preferences and expectations of participants for the return of individual research results within Project Baseline Health Study (PBHS). The PBHS is an ongoing, multicenter, longitudinal cohort study with data from four initial enrollment sites. PBHS participants are recruited from the general population along with groups enriched for heart disease and cancer disease risk. Cross-sectional data on return of results were collected in 2017–2018 from an (1) in-person enrollment survey (n = 1,890), (2) benchmark online survey (n = 1,059), and (3) participant interviews (n = 21). The main outcomes included (1) preferences for type of information to be added next to returned results, (2) participant plans for sharing returned results with a non-study clinician, and (3) choice to opt-out of receiving genetic results. Results were compared by sociodemographic characteristics. Enrollment and benchmark survey respondents were 57.1% and 53.5% female, and 60.0% and 66.2% white, respectively. Participants preferred the following data types be added to returned results in the future: genetics (29.9%), heart imaging, (16.4%), study watch (15.8%), and microbiome (13.3%). Older adults (OR 0.60, 95% CI: 0.41–0.87) were less likely to want their genetic results returned next. Forty percent of participants reported that they would not share all returned results with their non–study clinicians. Black (OR 0.64, 95% CI 0.43–0.95) and Asian (OR 0.47, 95% CI 0.30–0.73) participants were less likely, and older participants more likely (OR 1.45–1.61), to plan to share all results with their clinician than their counterparts. At enrollment, 5.8% of participants opted out of receiving their genetics results. The study showed that substantial heterogeneity existed in participant’s preferences and expectations for return of results, and variations were related to sociodemographic characteristics.

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The availability of broad health data generated through research, electronic health records, biobanks, and wearable devices has changed the health landscape in important ways [1, 2] . By transforming our understanding of the constituents of health, these endeavors have paved the way for harnessing big data and developing a richer understanding of the transition from health to disease [3, 4] . Central to these initiatives are longitudinal studies that allow for the collection and analysis of large volumes of data from participants. In addition to the logistical challenges inherent to such studies, their success is dependent upon the willingness of participants to engage in research, follow up for a predefined period, and derive a sense of value from their participation [5] . The motives for participant engagement, such as altruism or the desire to gain actionable health information, have emerged as important issues requiring characterization [6] .

In recent years, calls for a more participant-centric research approach have included support for the belief that participants have a right to their health data and that investigators have an obligation to return research results to participants [7] [8] [9] [10] . Prior work on returning single data types, such as imaging and genetic data, has shown promising but mixed results, with the opportunity to create value intermixed with cautionary notes of potential harms [11] [12] [13] [14] [15] . However, there remains a lack of clarity regarding the optimal mechanics of returning research results, with imaging and genetics paving the way while other data types remain in more nascent stages. Nevertheless, the enthusiasm for returning research results continues to grow, while several questions remain unanswered surrounding what to return, when, and how [16] [17] [18] .

The Project Baseline Health Study (PBHS) is a multicenter, prospective, longitudinal cohort study that aims to characterize the multidimensional nature of health and disease by collecting and analyzing deep and diverse types of participant data, including imaging, digital device, and molecular data (projectbaseline.com/). The return of multiple types of individual research results has been an important value within PBHS since its inception in 2017. The objective of the current study is to describe the baseline preferences and expectations of participants on the return of individual research results within the PBHS. As one of the first studies to return multiple domains of participant data to several thousand participants, these findings can inform efforts to return individual research results in a way that creates value for participation.

The PBHS is an ongoing, prospective, longitudinal cohort study across multiple sites; the initial sites were Stanford, Duke (two sites, one in Durham [Duke-Durham] and one in Kannapolis [Duke-Kannapolis]), and the California Health and Longevity Institute (CHLI) in the United States. The PBHS is a research partnership between Verily Life Sciences, Google, and the participating sites. The study was approved by the Western Institutional Review Board (WIRB) and local IRBs as required, and participants signed a consent form in order to participate in the study. The WIRB was the IRB for the study overall.

Research data collected from participants includes, but is not limited to, clinical and demographic characteristics, genetics, molecular, biochemical, imaging, behavioral, psychological, and physiological (e.g., a sleep sensor and study watch) data. Potential participants are identified through advertising, care provider recommendation, or community outreach activities. The goal is to recruit a population similar to the U.S. general census (standard cohort) with certain subcohorts enriched for the following disease risk areas: breast/ovarian cancer, lung cancer, and atherosclerotic cardiovascular disease. These enriched groups have an approximately 60% higher relative risk of disease compared to participants of the same age and sex, and were selected for enrichment because these are the leading causes of death in the U.S. and globally [19] . Participants have a two-day enrollment visit followed by annual visits for at least four years.

At enrollment, participants review and sign a consent form that indicates that participants will receive results from certain tests conducted as part of the PBHS. Participants are notified that the PBHS is a research study and not clinical care, and that it is not possible to fully optout of receiving some returned results. The consent form indicates that participants will have the option to decide whether they would like to receive genetic results. The return of research results policies and procedures were informed by a PBHS Return of Results Committee, which comprised clinicians, researchers, and participant advocates across the participating sites and external groups.

Data for the current study were collected from three sources: (1) enrollment in-person survey, (2) benchmark online survey, and (3) participant interviews. The enrollment in-person survey was administered during the participant's first two-day visit. Data were collected by trained study staff for all participants enrolled between 3/30/17 and 11/30/18 on a case report form. The benchmark online survey was made available to participants one to 11 months postenrollment through a digital app or website; data collected from 3/29/18 to 11/30/18 were included in this analysis. During the period between these two surveys, most participants received traditional clinical lab results (e.g., complete blood count) from the study, and some participants received results from imaging and onsite testing that were deemed to be critical or time sensitive (e.g., stress echocardiography results suggesting ischemia, or chest x-ray with large pulmonary nodule). Semi-structured interviews were conducted from 10/20/17 to 12/7/ 17 among a convenience sample of participants across sites before participants received any results. These interviews were conducted by the same study team member for approximately one hour with each study participant, and the interviews were later transcribed and analyzed independently by two other study team members.

We examined three main outcomes: (1) preferences for type of result to be added next to the portfolio of returned results (benchmark survey), (2) participant plans for sharing returned results with a non-study clinician (benchmark survey), (3) choice to opt-out of receiving genetic results (enrollment survey). The survey items for the main outcomes were as follows:

(1) Which of the following results would you be most interested in getting back next? (response options: genetics, microbiome, vital signs, physical assessment, cognitive assessments, heart imaging, eye imaging, sleep sensor data, study watch activity data), (2) Does the participant wish to opt out of genetic return of results? (response options: Yes or No), and (3) Which results from your site visits would you be likely to share with a doctor or nurse if you got them back? (response options: all results, results I do not understand, abnormal results, results my doctor or nurse is interested in having, results that are relevant for an existing health condition, I do not plan to share results with a doctor or nurse, I do not have access to a doctor or nurse).

Other outcomes in the benchmark survey included participant preferences regarding how results should be returned (i.e., phone call, email, mail or text), the benefits anticipated from receiving results (i. The responses to all survey questions were mutually exclusive (i.e., participants could only select one answer) aside from the outcome question on sharing results, which allowed multiple answer selections.

The semi-structured interviews included questions on expectations and preferences for the return of research results, including their expectations on what they would receive and how it would be returned.

Descriptive statistics are presented for survey responses, stratified by sociodemographic and clinical covariates: sex, age, study site, cohort (enriched or standard), self-reported race (white, black, Asian, or other) and ethnicity (Hispanic or non-Hispanic), income, and education level. For the three main outcomes, multivariable logistic regression models adjusted for these a priori selected sociodemographic and clinical covariates, based on the researcher's knowledge and prior literature, are presented as odds ratios with 95% confidence intervals [7] [8] [9] [10] [11] [12] [13] [14] [15] . All quantitative analyses were conducted on Python (v2.7.1); a nominal p-value (i.e., unadjusted for multiple comparisons) of <0.05 was considered statistically significant.

Transcribed interview data were analyzed using an inductive thematic analysis approach [20] . Two authors (Sayeed, Wong) independently examined each transcript to identify and categorize relevant themes according to their frequency of appearance in the transcripts. The codebook was modified through an iterative process to account for newly emerging and unanticipated themes, consolidate themes, and revise code definitions. Content identified from the transcripts was sorted into different content sheets by themes and subthemes using Google Sheets, and coding disagreements were resolved via consensus. Illustrative quotes are presented to complement the quantitative results. Given the exploratory nature of this study, we did not apply adjustment for multiple comparisons.

The baseline enrollment survey included 1,890 participants, representing all those enrolled in the study at the time of analysis. The majority were female (57.1%), white (60.0%), and reported a yearly income over $50,000 (Table 1) . Approximately one quarter (24.5%) had attended college and 26.2% had an advanced degree. Similar distributions were seen in the benchmark survey (N = 1,059, response rate 56.0%). In the subset who were interviewed (N = 21), 76% were white, 62% were advanced degree holders, and 52% were men. The overall study participants were similar to the general U.S. population with the exceptions of higher income and education distributions (Table 1) . 

When selecting among options of data types that participants preferred to receive after having received initial medical testing results, genetics (29.9%), heart imaging (16.4%), study watch (15.8%), and microbiome (13.3%) were the most common selections (Table 2) . Participants 

When asked to describe how they felt about the possibility of receiving results back from their site visits, 54.9% of study participants said they were "excited to learn more about [their] health," and 36.4% said they were "curious about the results." Among survey respondents, 7.4% said they were "nervous" about receiving their results. The most commonly selected expected benefits of receiving results were: "learning new things about my health" (72.5%), "improving my health" (72.0%), and "identifying my risks for disease" (70.1%). Fewer participants anticipated the benefit of having ownership of their data (38.1%).

With regard to the structured interview results (N = 21), while some participants desired and expected to receive all data related to their health returned to them, including in raw form, others expected only results that were actionable (Table 3) . Other key themes from the Table 3 

• Desire to feel empowered to act on results: "Really, the whole thing is to empower me as an individual. 

In the benchmark survey (n = 1059), 40% of participants (n = 426) reported not wanting to share all returned results with their own (i.e., non-study) clinicians (Table 4 ). Black (OR 0.64, (Table 4 ). Compared to participants with advanced degrees, those with a high school diploma or less were less likely to report wanting to share abnormal results (OR 0.24, 95% CI: 0.08-0.69). Younger participants were more likely to report wanting to share results they did not understand than their older counterparts. Differences were noted by study site; participants at Duke-Kannapolis were more likely to report wanting to share all results and less likely to share abnormal results.

Interviewed participants stated that they did not expect clinical recommendations with their returned results, though they did express a desire to see their data benchmarked against normative data to inform whether they should see their own non-study clinician: "I expected to see the data with norms. Then if I saw something that was outside of the norm, I could decide to follow up with my medical practitioner. I wasn't looking for any sort of recommendations, unless there was something that was egregiously wrong" (Table 3) .

At enrollment, 5.5% of participants opted-out of receiving their genetics results (Table 5 ). Participants at the Duke-Durham (OR 8.62, 95% CI:4.44-16.73) and CHLI (OR 2.29, 95% CI: 1.06-4.96) sites or those with a high school education or less (OR 3.37, 95% CI:1.44-7.91) were more likely to opt out of receiving their genetic results.

In a diverse sample of participants within the Project Baseline Health Study across four U.S. sites, individuals were excited and curious about receiving individual research results across various types of data streams. The majority of participants elected to receive their genetics results, while perhaps surprisingly, over a third said that they would not share all their results with their own clinicians. Participant expectations were heterogeneous, with younger participants preferring to receive their genetic results returned next while other participant preferences differed by sociodemographic characteristics.

Most participants in the PBHS were excited and curious to learn more about their health through the return of research results, mirroring previously described eagerness and curiosity about returned research results [21] [22] [23] . A growing literature recognizes that returning results serves a two-fold purpose: participants' enthusiasm for returned results can help maintain their engagement for meeting the scientific goals of a study, while researchers can fulfill the increasingly accepted ethical obligation to share participants' personal health data with them. Though the processes for returning individual results are in nascent stages of development, the scientific community has begun convening groups to outline recommendations and frameworks to guide the field, such as the proposed criteria of validity and actionability for deciding what to return [24, 25] . Our qualitative results support the need for continued development of processes to return research results and highlights the importance of asking participants about their preferences and expectations early in the study protocol. Determining what is actionable and how to share data to facilitate appropriate action will require further work, especially when considering non-standard of care research tests for which there is no precedent consensus [24] .

While participants were enthusiastic about receiving research results, 40% of survey respondents reported not planning to share all of their results with their non-study clinicians. Participants in the PBHS are voluntarily consenting to share their personal health data for research purposes, so their choice to not share all of their returned data with clinicians was surprising. Lower enthusiasm for sharing results with clinicians among black, Asian, and lower income participants may reflect differing levels of trust in healthcare and research, and suggests a need to monitor the impact of returning results on long-standing and continued health inequities, many of which have been exacerbated during the COVID-19 pandemic [26, 27] . Moreover, prior work has hinted at mixed readiness among clinicians to receive research results; concerns include inadequate physician time for processing large quantities of research information [28] [29] [30] [31] . Some participants stated they would only share abnormal results or results relevant to existing medical conditions, which could reduce the burden placed upon clinician time. Other strategies include co-designing processes with clinicians to understand how to incorporate returned research results into clinical workflows, such as within electronic medical records or by utilizing other team members (e.g., genetics counselors) [32, 33] . The diversity of participant preferences and expectations will be a key challenge to returning research results in large clinical studies [34] . Participants in this survey differed not only in how much data they wanted returned, but also in the types of data they wanted to access. The heterogeneity of participant expectations on receiving results is similar to the diversity of patient preferences seen in clinical care, including differences seen by race and ethnicity [35] [36] [37] . Technology and data science advances can support individualizing how data are returned to participants, such as allowing participants to toggle result reports on and off or to select preferences on how their results are returned [11, 38] .

While participant preferences should be considered, there may be situations in which not returning results would be ethically inappropriate (e.g., a life-threatening finding with treatment options) where the duty to warn may come into conflict with participant wishes. The line is poorly defined between research participant autonomy to receive what they deem desirable, and the responsibility of researchers to highlight for participants the implications of clinically important results. Delineating what should be responsibly returned is even more difficult for results derived from non-standard data types, such as wearable device data or metabolomic results, where the limits of normalcy, or even the evidence for any sort of benefit, are illdefined. Additionally, characterizing the ethical issues and complexities surrounding sharing potentially life-threatening results with relatives will also require further work [39] . In all cases, the importance of clearly explaining to participants the implications of choosing whether to receive individual research results cannot be overstated.

The results of this study should be interpreted in the context of several limitations. While the PBHS sample for this analysis included a diverse group of participants from multiple U.S. sites, the preferences and expectations of participants who chose to join this study may not be representative of research participants in different studies or other segments of the general population. While our study population was well matched to the overall U.S. population in most regards, differences were seen in income and educational levels, particularly among the interviewed subsample with higher proportions of white and highly educated individuals. Examining preferences by participant characteristics, including race and ethnicity, is critical given the historic and persistent racial and ethnic disparities in the quality and access to health care in the United States [40] . Despite these notable differences, interviewees in-depth insights provide richness to the quantitative results. Finally, the preferences and expectations described in this study were collected before participants had received results in most cases; participants' perspectives and planned actions, such as sharing results with their clinicians, may change as results are returned in the study.

The novelty of the PBHS includes the commitment to asking participants directly what research results they would like to see returned and returning individual research results as a core element of the research endeavor. These early findings on the participants' preferences and expectations for receiving research results will help the PBHS investigators refine the process. These data may also inform the broader research community in discussions about policies and practices that will promote a culture of partnership between researchers and study participants. The need for such partnerships will be accelerated as learning health systems align science, data, and clinical care [41] , and biobanks accumulate and test a wider array of samples [42] .

In the midst of growing rhetoric to free data, the diversity of participant perspectives and the nascent stage of returning research results at scale underscores the challenges ahead. These findings among a national cohort of participants in the PBHS provide an empirical basis for how research data can and should be returned in ways that may add impact and value to healthcare and research participation. While general trends in preferences exist as a function of age, race, ethnicity, sex, and geography, an important realization is that there is no substitute for asking people about their preferences.

Supporting information S1 File. Return of individual research results and data dictionary. (DOCX) S1 Data. Plos one benchmark survey data (pre-RoR).

(XLSX)

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