Learning from the Return of Clinical Test Results: Opportunities and Limitations

The health care enterprise has considerable experience with the generation, interpretation, and return of clinical test results. In most clinical contexts, the flow of information passes through a clinician before reaching the patient. The clinician's role, therefore, has been one part gatekeeper and one part interpreter. It is important to note, however, that information technology is increasingly changing this pattern. In many health care systems, patients can access laboratory test results directly through patient portals to electronic record systems, thereby reviewing these data without a clinician present to explain the results and their significance (AHA, 2016). Furthermore, health systems vary in the degree that clinicians are required to review or annotate results before they are released to patients. Direct-to-consumer testing represents another model for the direct return of results to an individual, one in which a clinician may not even know that a test has been conducted until the patient presents the result report to their physician (O'Connor, 2016).

While the health care delivery experience may offer lessons for the return of research results, this is not to say that best practices for communication are always (or even usually) applied in clinical practice. Research indicates that the current level of information provided with clinical test results may be insufficient to enable patients to understand their meaning (O'Kane et al., 2015). Clinical biomarker results, for example, are generally returned in numerical or tabular form with a standard reference range. However, recent evidence suggests that many patients struggle to determine whether a result is inside or outside of the standard reference range, which is the most basic form of understanding needed for meaningful use (Zikmund-Fisher et al., 2014). Sometimes (but not always) results are also accompanied by an interpretive statement from the ordering clinician, but the language used in such statements may vary across clinicians and situations. Despite this, there are situations in which clinical results are returned with additional contextual information where the purpose of the test and the information generated during the test are addressed. For example, in clinical genetics patients are often given substantial contextual information (e.g., counseling, the meaning of a negative result, clear statements of known impact of particular mutations) to help them understand their results (Haga et al., 2014). The same practices may be appropriate for research-based genetic testing, although research results may be associated with greater uncertainty, which may require further clarification.

Challenges communicating clinical test results and other medical information effectively may stem, in part, from gaps in health literacy¹ and other forms of literacy, such as graph literacy and health numeracy.² In 2006 the National Center for Education Statistics released a National Assessment of Adult Literacy and found that “the majority of adults (53 percent) had intermediate health literacy while about 22 percent had basic and 14 percent had below basic health literacy” (National Center for Education Statistics, 2006, p. v). Extensive research shows that low health literacy, poor numeracy, poor graphical literacy (Joint Commission, 2007), and language barriers all impede an individual's ability to interpret and use information such as test result communications (Rodríguez et al., 2013; Zikmund-Fisher et al., 2014, 2017). This underscores the importance of understanding the limitations that poor literacy may impose on understanding and emphasizes the importance of clear communication in the provision of health information (Joint Commission, 2007), including clinical and research test results. To address literacy and numeracy barriers, such information needs to be provided in a format and with content that is accessible to the target audience (Parker et al., 2016). This may entail

• creating materials in users' primary languages and considering language-based sources of misunderstanding to address language barriers,
• creating materials that reflect participants' preferences regarding terminology,
• using plain language to overcome low literacy (CDC, 2016; IOM, 2014), and
• using evidence-based formats that facilitate understanding of quantitative information by those with low numeracy and graphical literacy (IOM, 2014).

In addition, the National Academies of Sciences, Engineering, and Medicine's Roundtable on Health Literacy published a perspective on health literacy and precision medicine, which concluded that “participant input into the crafting of clear, navigable, and useful messages and processes” is a hard-learned lesson from the field of health literacy (Parker et al., 2016, p. 3). While those in the field of health care have acknowledged these gaps in practice which inhibit patient understanding and have made strides to correct this, there are still areas where improvements can be made to the processes of clinical test return and messaging. Research has the opportunity to learn from both the good and the bad in clinical test return. Doing so will allow the research enterprise to shape the return of research results into a practice that simultaneously benefits the participant most fully and is done in a way that does not burden the investigator. However, research sponsors and funding agencies will need to support an assessment of best practices and how to apply these to a research context first.

CONCLUSION: Many existing practices in the return of clinical results are potentially applicable to the return of individual research results, but they will need to be critically evaluated before they are adopted in the return-of-research-results context.

Learning from Current Practices in Return of Individual Research Results

Research results differ substantially from clinical test results in a number of ways, which limits the degree to which clinical experience can offer guidance on the return of research results. Most notably, research results are often associated with a greater degree of uncertainty as a result of incomplete scientific knowledge, and the uncertainties present at the level of individual results are even larger than the uncertainties present in aggregate results. However, as research continues, quality management systems are adopted by research laboratories, and evidence accumulates, the uncertainty in research test results can be reduced.

When patients' results are returned by the treating clinicians or clinical laboratories, the results are often accompanied by well-established population distributions or reference ranges³ that enable interpretation by the patient and clinician (Medscape, 2014). Expected reference ranges for clinical tests (e.g., blood counts) are known because the results are generated by standardized procedures used across broad populations of patients which allow for the establishment of normal result ranges for different patient characteristics, such as age or gender. In contrast, because of the significant variability in practices used in research settings, a result may need to be accompanied by documentation on what was actually done or not done in order to evaluate its meaning (and potential value or actionability). Moreover, reference information (e.g., standard ranges) for research results is often unavailable, non-representative, or unreliable for understanding whether a result is normal or abnormal and for guiding decision making. As discussed in more detail later in this chapter, research teams will need to think carefully about what reference information is available and potentially valuable for use in communicating with participants about the meaning of their individual results.

Uncertainty is difficult to communicate, particularly when it relates to something that is already probabilistic in nature, such as genetic-related risk; therefore, uncertainty is often ignored (Han et al., 2011). A critical part of the return of research results, uncertainty needs to be conveyed effectively, or else investigators risk the participant putting too much or too little trust in the results. As discussed in more detail later in this chapter, attention needs to be paid to providing reference information that enables participants (and, in some cases, their treating physicians) to be able to interpret and understand the potential (or lack thereof) for using the research results.

Although the return of individual results is not currently widespread among research studies, certain investigators are already returning research results to individual participants. This is particularly true in the fields of genetics and environmental health (discussed in the sections “Returning Individual Genetic Research Results” and “Environmental Health and the Return of Individual Research Results”). These fields' experiences with the return of research results may be valuable in the development of best practices and guidance for other types of research results.

Environmental Health and the Return of Individual Research Results

The return of research results from environmental health biomonitoring¹³ studies is well established both in the literature and by guidelines proposed by expert groups (Brody et al., 2014; Dunagan et al., 2013; Exley et al., 2015; Haines et al., 2011; Judge et al., 2016; Morello-Frosch et al., 2009; Quigley, 2012). The return of results in this field is done because the research participants generally have a significant interest in learning their individual research results for their own use and safety (Brody et al., 2014). A key consideration in determining how best to report results in an environmental monitoring study is whether a known clinical range or action level has been established for the analyte being assessed (a point we reinforce later in this chapter). Where a clinical or preclinical effect is known, this knowledge allows better guidance to be provided to participants, particularly in terms of follow-up. As is the case with exposure to lead or arsenic, acceptable blood levels and public health procedures are defined with the goal of mitigating future exposure (CDC, 2018; WHO, 2017), although it is not uncommon for such guidance to change over time. For example, The Maternal–Infant Research of Environmental Chemicals study used predetermined guidelines to define its return and communication strategy, specifically, whether a result exceeded normal levels and might be associated with a health risk (Haines et al., 2011). However, it is not uncommon for a chemical, pesticide, or other environmental contaminant to lack reference-range information, (i.e., an analyte that is not well characterized in a population) or to have differing reference ranges or other bias in datasets that can cause challenges in interpretation (NRC, 2006). Therefore, determining the meaning and clinical interpretation of such test results can be a challenge, and “reference ranges do not provide conclusions on safety or risk. Presenting that fact and other limitations is an essential aspect of communicating reference-range information to individuals, the general public, and organizational decision-makers” (NRC, 2006, p. 151).

The return of research results with unknown clinical significance is also practiced in environmental health research. In 1999 the Household Exposure Study, which focused on identifying 89 endocrine-disrupting compounds, grappled with questions of whether the results (both from biomonitoring and environmental samples) should be returned to participants, including those results with unknown clinical meaning. Ultimately, after consideration of ethical guidelines and in consultation with community members, investigators allowed participants to access their individual and household results (Brody et al., 2007, 2014; Dunagan et al., 2013). Similarly, in 2004 the University of Michigan Dioxin Exposure Study, which conducted tests for the presence of 29 dioxins, furans, and polychlorinated biphenyls in participants' blood, household dust, and residential property soil, also gave participants the option to choose whether they would receive the results from each of their samples (Garabrant et al., 2009). This option was provided for two key reasons. First, regulations were not available for the dioxin content of household dust, nor were medical guidelines available for the interpretation of serum dioxin levels at the time. Second, the researchers were aware that the disclosure of soil levels to property owners could cause those participants financial harm by affecting their property values.

In general, this literature concludes that the unknown should not dissuade investigators from returning results with uncertain meaning because “what little evidence we have suggests that a globally uncertainty-averse public is a myth; responses [to receiving uncertain information] vary widely across the population” (NRC, 2006, p. 207). This variability does, however, emphasize the need to return information with the input from the community or study population as results can often have community-wide implications or health risks.

As the committee heard in discussions with environmental health researchers, those participating in environmental exposure studies frequently want to know their results because they are the ones carrying the products of these exposures in their bodies.¹⁴ For this reason, investigators in this field may feel a greater need to return such results. Such studies also frequently take place in communities where several households are affected and, therefore, the results of the study will likely be translatable to many in the community. To this end, investigators may use community partnerships in the design of communication plans. In a study by Erin Haynes of the University of Cincinnati, community engagement was used to develop the methods of communication used in the return of results (Haynes et al., 2016). Working together, the study team and community members developed easy-to-read graphics and written materials tailored to the reading level of the recipients as well as a comparison to help in the interpretation of their results (i.e., comparing a recipient's results with those from other studies or for other children). The research team found that including community input in the development of its dissemination plans helped them translate biological data into a format that was usable by the target audience. Haynes et al. concluded that “scientists should include community partners from the target population in the development of research and data disclosure strategies in order to enhance the quality of research, to support the rights of the study participants to know their individual results, and to increase environmental health literacy” (Haynes et al., 2016, p. A26). See Box 5-1 for select engagement and communication practices for the return of research results in environmental health.

BOX 5-1

Select Engagement and Communication Practices for the Return of Research Results in Environmental Health.

CONCLUSION: Current research projects that return research results to individual participants use a variety of practices that have been tailored to reflect differences in study goals, populations, types of results, and other factors.

Applying Principles for Effective Communication to the Return of Research Results

Applying existing principles for clear communication represents a concrete strategy for improving the quality of return-of-results practices. While the body of evidence is still small, these issues have begun to be examined in health communication and environmental health studies. California law, for example, requires that biomonitoring results be made available to participants, and the state has conducted usability testing for content, allowing others to benefit from this work (Biomonitoring California, 2018; Brown-Williams and Morello-Frosch, 2011). More empirical testing is needed to guide stakeholders, but there is work already occurring in this arena (as discussed above). IRBs would benefit from using best practices and reviewing the literature outside of their field; e.g., biomedical scientists can benefit from the existing guidance in environmental monitoring in developing their return-of-results communication plans. IRBs do not need to rely on gut opinions when evidence-based guidance exists and can inform participant and community input in plans. The key principles in communication that have been identified include (1) taking audience characteristics and needs into consideration and (2) having a clearly defined communication objective (i.e., what cognitive, emotional, motivational, or behavioral outcomes should ideally result from the communication) (Haga et al., 2014; Nelson et al., 2009; Schiavo, 2014).

Consideration of audience characteristics and needs includes taking into account how much background knowledge a research participant has (i.e., what he or she knows about a particular disease or condition, about research, etc.) and what kinds of experiences the participant has had in the past. Research studies need to approach all participants and every community with respect and cultural humility. Doing so supports the development of trust between researchers and participants, and such trust is especially important given the known history of exploitation in racial and ethnic minorities and intellectually disabled individuals (Carlson, 2013; Corbie-Smith et al., 2002; Yancey et al., 2006). Because different stakeholders will have varied perspectives and preferences, those differences need to be considered and weighed. It may be necessary to design separate return-of-results communication plans for different stakeholder groups, since something designed for one audience is likely to be non-optimal for other audiences. As a result, a one-size-fits-all approach will rarely be effective in results communication.

Research studies are designed to produce generalizable information that is applicable to the broad population and results have meaning to multiple users, from the participants who contributed to the study to the investigators who ran the study. Results can sometimes be interpreted as a characteristic of an individual participant rather than an aggregate result reflective of a broad population, making it relevant or meaningful to family members, a physical community, or a demographic group, which may have implications for the communication approach. For example, the discovery of a genetic variant in a participant provides information about that individual participant's future disease risk but, if the variant is heritable, the discovery may also offer information about family members' risks and lead to generalizations about a group's risk. Similarly, an environmental exposure result may be relevant not only to the participant, but potentially to others who share that environment (e.g., family members, neighbors, coworkers).

Using layered presentations of information is a key communication approach for meeting different needs. For example, many communications should start with a clear and concise summary of the primary points that is designed to be maximally understandable to all users. However, providing access to more detailed information (which may be more difficult to understand) is often beneficial for users with greater personal interest, literacy, or numeracy skills. When participants have different informational baselines and literacy levels, research teams will need to consider how much background information to provide to each audience. For some people, “less is more,” while for others, “more is more” (Arcia et al., 2016).

When returning results to participants investigators need a clearly defined communication objective and should consider what specific change in knowledge, beliefs, motivation, or behavior is intended. The objectives of the communication will need to take into account the individuals' needs more than the investigators' needs, and they should be focused, with just one or a few objectives. A general truth is that the more one attempts to convey in a communication, the less effective that communication is likely to be (Heath and Heath, 2007).

Good design practices can significantly improve people's ability to overcome communication barriers. For example, the CDC's Clear Communication Index identifies key characteristics that enhance and aid people's understanding of information. These include the use of materials translated into the recipient's primary language, use of plain language with minimal jargon, use of good visual design principles, and use of evidence-based visual displays of data (CDC, 2016; Kosslyn, 2006; Plain Language Action and Information Network, 2018; Tufte, 2001). These practices represent minimum standards that all results communications (including clinical results) should achieve. As such, they should be included as part of training initiatives for investigators and clinicians as the research enterprise works to build the necessary expertise for effective return of results.

Models of Consent

Current consent processes are not standardized and are frequently inadequate to ensure understanding on the part of all participants. In fact, some research suggests that clinicians rarely meet even the minimum standards for disclosure necessary for the purposes of obtaining true consent (Hall et al., 2012). Unfortunately, many investigators do not have appropriate training in consent practices. Furthermore, they can (much like participants) be susceptible to therapeutic misconception and may, as a result, convey biased messages to participants (Larson et al., 2009).

In selecting a consent model and administering consent, investigators may want to consider how technology can facilitate the consent process. For example, technology can be a particularly helpful way to incorporate the principles of health literacy (as discussed previously). Health literacy has a strong impact on what individuals understand and how they use information related to health care and decision making. As such, investigators would benefit from capitalizing on best practices in health-literate informed consent (see Box 5-2). “The challenge is finding practical, non-onerous ways to respect persons' choices that have minimal negative effects on the science. Information technology may provide new opportunities to implement informed consent with minimal intrusion” (Grady et al., 2017, p. 857). For example, technology-assisted consent, such as the Apple Research Kit for mobile devices, which includes a layered approach to consent in which the formal consent document is augmented by a visual, animated sequence, helps the user better understand the consent contents (ResearchKit, 2017).

BOX 5-2

Best Practices for Health-Literate Informed Consent Related to the Return of Individual Research Results.

Additionally, video-aided consent, like that used in the ADAPTABLE trial, can contribute to participant understanding (ADAPTABLE Asprin Study, 2018; Grady et al., 2017). Tele-consent is another method that enables researchers to remotely video-conference with prospective research participants. With tele-consent, investigators create a display that interactively guides participants in real time through a consent form, which they then electronically sign (Welch et al., 2016). However, while the use of electronic methods for consent may offer advantages for the return of research results in terms of convenience as well as providing varied approaches (e.g., use of multimedia interactive formats) for increasing understanding of the information and making possible structured assessments of that understanding, there are also a number of challenges that need to be considered (Welch et al., 2016). These challenges include the fact that many people do not read terms of agreements on computers and mobile devices, there is a dearth of evidence regarding the advantages and disadvantages of electronic methods in terms of understanding of information, and since there are no face-to-face visits, verifying the identity of the individual giving consent may be difficult (Grady et al., 2017; NPR, 2014).

In addition to ensuring that investigators are meeting the communication needs of participants with health-literate consent, investigators and IRBs will need to consider the trade-offs among consent models and formats, no matter which model of consent is used, whether traditional paper or electronic format. See Table 5-1 for an example of how the advantages and disadvantages of consent models were assessed for the return of secondary findings. Table 5-1 discusses these secondary findings (also referred to as “incidental findings”) and consent. The committee considers secondary findings to be results that can be anticipated on the part of the investigator and that considerations similar to those presented in this table can be made for any anticipated result, whether or not it is the primary aim of the study or test. Fully assessing the models of consent and closing gaps in communication during consent, particularly with the added considerations that accompany returning results, will require training for investigators and clinicians. Such training will take concerted effort, but it has the potential to enhance benefits, minimize harm, and build trust in the research enterprise.

TABLE 5-1

Potential Advantages and Disadvantages of Models of Consent to Return of Secondary Findings.

CONCLUSION: Details regarding the return of individual research results to participants are currently only addressed during the consent processes on an ad hoc basis, creating inconsistency across studies and institutions and inadequately setting participant expectations.

CONCLUSION: How the return of individual research results is, or is not, addressed in the consent process affects participant expectations.

CONCLUSION: The heterogeneity of research study designs and populations means that different consent processes will be appropriate in different situations, but regardless of the type of consent process, clear communication appropriate to varying levels of health literacy is essential.

Recommendation 9: Ensure Transparency Regarding Return of Individual Research Results in the Consent Process.

In the consent process, investigators should communicate in clear language to research participants

A.

which individual research results participants can access, if requested, including any results participants have a legal right to access under HIPAA, and how to request these results; and

B.

which individual research results, if any, will be offered to participants and why, and the participant's option to decline to receive their research results.

C.

If results are going to be offered, the following elements should also be communicated during the consent process:

1.

the risks and benefits associated with receiving individual research results;

2.

conditions under which researchers will alert participants of urgent results;

3.

at what time and through what process results will be communicated to participants;

4.

whether the results will be placed in the participant's medical record and whether the results will be communicated to the participant's clinician; and

5.

when relevant to the research protocol, the participant's option to have results shared with family members in the event the participant becomes incapacitated or deceased.

Facilitating Understanding of the Meaning and Limitations of Results Through Reference Information

Having access to information is not the same as being able to understand and use that information. In particular, studies in both the consumer product marketing and medical decision-making fields have shown that people find it difficult to interpret unfamiliar data in the absence of relevant reference standards (Hsee, 1996; Zikmund-Fisher et al., 2004). As a result, hard-to-evaluate information is often ignored or not used in decision making. Many recipients of clinical test results are unable to interpret them because of a lack of familiarity with test characteristics or the possible range of test outcomes. Furthermore, even when recipients know what the result is, they may not understand its practical meaning (in terms of whether concern or action is appropriate) (O'Kane et al., 2015).

In sharing individual research results with participants (especially when results are offered as part of a return-of-results plan), research teams need to communicate not just what research or test was done, but why it was done and how. To improve the meaningfulness of research test results, especially those that are difficult to understand or that are generated from tests that are not commonly used, research teams need to provide clear cues regarding (1) how much participants should trust the result and (2) what the result means or what is not known about the meaning of the result. This is because the types of laboratory tests used in research studies may generate results that are more likely to produce hard-to-evaluate data because these tests are novel, their analytic validity is unknown or being established, or their clinical validity is unknown (see Chapter 3 for more details). To help make it easier for participants to understand results, investigators need to pay attention to what reference information (e.g., standard reference ranges, comparative risks, or categorization information) is needed or appropriate for each type of result communication. The information provided with the result may dictate recipients' understanding and actions even more than the result itself. In some cases, results may need to be accompanied by multiple types of reference information (when available) to enable participant understanding.

To be clear, providing reference information for a result is not the same as providing personalized interpretation, such as clinical guidance. Clinical guidance requires integrating a research test result into the participant's individual circumstances (e.g., known medical conditions, family history). While such integration is sometimes expected in certain study contexts, investigators may not be clinicians or may not be familiar with the specific health of the participant, in which case providing clinical guidance would not be appropriate. Additionally, clinical guidance may be labor intensive, requiring investigators to tailor the research results and reference information to each individual participant's circumstances. Reference information, however, is a function of the test and the circumstances of the study but not of the individual. Consequently, providing reference information is scalable: investigators can more easily return results to a large number of participants because, in general, the reference information is applicable to all of them or to all similar participants receiving the same test. Emphasizing the identification and communication of appropriate reference standards is hence a cost-effective way of improving return-of-results communications.

Relevant reference information may be well established and standardized or may be unknown. For example, environmental contaminants such as radon and arsenic have established action thresholds or other benchmarks set by the Environmental Protection Agency. Similarly, standard clinical tests have established reference ranges (often interpreted as the range of normal values) and sometimes even pre-defined critical values (i.e., values high or low enough that a laboratory is obligated to immediately notify treating clinicians about the result to minimize associated risks; an example would be an elevated glucose level). In a genetics context, the impact of having a known BRCA1 mutation on lifetime breast cancer and ovarian cancer risk is relatively well established when family history is also known (Paul and Paul, 2014). Other times, however, reference knowledge is known but no standard guidance is available; i.e., the reference information that is available cannot be generalized to a population. Alternately, reference information may not be well understood or may be completely unknown in research contexts. For example, safe or dangerous levels for a particular toxin or novel biomarker may not have been established. Dose–response relationships may be unknown or difficult to estimate for particular populations. Even relative standards, such as percentiles compared to reference distributions, may be unavailable or incorrectly used if no previous studies exist or if previous studies involved different populations, such as different racial or ethnic groups (Holland and Palaniappan, 2012). Genetic variants often have no clear significance or correlations with health outcomes, and many times the prevalence of the variants in different populations is unknown (Caswell-Jin et al., 2017; Saulsberry and Terry, 2013).

The more that is unknown about reference standards for a particular result, the more that the participant and either the investigator or the individual performing the communication should have a two-way communication to clarify “what this result means for me.” Clarification of meaning via dialogue is important not merely to improve participant understanding, but also to prevent an inaccurate interpretation or over-interpretation of results. When reference standards for a result are not known, investigators should weigh the benefits and risks of return and consider whether a return of aggregate results only would be more appropriate than a return of individual results. Regardless of whether aggregate or individual results are returned, the fact that reference information does not exist should be explicitly communicated to participants.

When developing a return-of-results plan, one explicit step should be the identification of appropriate reference information to be provided to participants. The reference information varies by the nature and type of results generated and by how informative the result is to the participant. Box 5-4 summarizes the kinds of reference information that may be appropriate to provide to participants, given the types of results that laboratories generate. Laboratory results are of two distinct types—continuous (e.g., biomarker levels that may vary across a continuous range of possible values) or binary (e.g., presence/absence of genetic variant or marker). In the clinical laboratory, these types of results are referred to as quantitative and qualitative results.

BOX 5-4

Types of Reference Information.

Communicating Key Takeaways, Including the Actionability of Individual Research Results

When returning results to participants, a single, clear takeaway message is important. Being given information and not knowing whether or how it should be acted upon can be disconcerting and potentially emotionally harmful to participants (Shani et al., 2008). Consistent with the ethical principles of beneficence and non-maleficence, research teams have some obligation to minimize and mitigate such potential harms. When results are being offered to participants, the most straightforward way of offering a single, clear takeaway message is to provide a concise statement of why the results are being returned and a clear summary of the meaning of the results based on the research team's current knowledge of the test performed at that point in time. Given that scientific knowledge is constantly evolving, especially in terms of understanding research results, investigators should clarify both the date when the message is being generated by the study team and how likely or unlikely it is that the interpretation of the result might change in the future. In addition, given the evidence discussed above of substantial language and literacy barriers to comprehension, the importance of providing action steps (if appropriate) clearly and in plain language cannot be overstated.

The takeaway message can vary depending on the state of knowledge regarding the test result and its implications. When the meaning is uncertain (i.e., the investigators do not know how to interpret the result), this uncertainty and the fact that no action can be recommended is the takeaway message. Such a clear message of no recommended action needs to be stated explicitly to prevent people from making inaccurate assumptions. In some cases, the meaning of the result may be known, but it has no implied action. An example of such a result would be the return of “normal” results from clinical testing that was conducted in the course of a research study. However, determining the appropriate takeaway message is not always so straightforward, such as when a genetic variant of unknown significance is identified in genetic testing. A communication with no recommended action can be particularly difficult because people may not believe that researchers would return a result but not want the participant to take any further action; there is also the issue of the potential “emotional burden, concern, or worry of knowing that there is nothing [the participant] could do about it” (Hyams et al., 2016, p. 5). Providing such information can have both positive effects (e.g., by drawing a participant's attention to a particular disease risk) and negative effects (e.g., inducing anxiety or motivation to pursue unnecessary screening tests). In other cases, the result may indicate the need for possible or even highly encouraged action.

In the consent document, key information is optimally included at the beginning of the consent document and will contain a “concise and focused” description of the research and summarize the project information that is most important to potential participants in making their decision whether to enroll in the study (Federal Register, 2017). Similar methods (i.e., requiring concise and focused descriptions of the findings and its implications) should be applied in the return-of-results communications.

When participants will need to carefully consider a potential action (e.g., because of trade-offs), the more that a communication can identify both why participants should consider actions and why they might not want to do so, the more useful the communication will be. In addition, if a result implies an action that is highly encouraged, acknowledging the potential barriers or challenges to undertaking these actions is beneficial by helping to frame realistic expectations and prepare participants to overcome those barriers, when appropriate.

Guiding principles for the design of return-of-results procedures parallel the best practices for consent procedures and support the importance of providing key takeaway messages. Best practices need not be developed at the level of the individual investigator alone. Changes in community, federal, or industrial practices may be needed to develop better guidance for how the research committee needs to approach these situations. To deal with the fact that research participants often struggle to make sense of consent documents, the 2018 proposed revisions to the Common Rule mandate that consent documents provide a “key information” section at the beginning of the consent document that contains a “concise and focused” description of the research and summarizes the project information most important to potential subjects in making their decision whether to participate (Federal Register, 2017). Similar remedies (i.e., requiring concise and focused descriptions of the findings and its implications) should be applied in the context of returning research results.

CONCLUSION: Individual research results need to be communicated with a clear takeaway message that includes a statement of actionability (or lack thereof).

Communicating Caveats and Uncertainties

Previous chapters discussed multiple reasons why research results often have substantial variance or potential for error which limits interpretation and usability for an individual participant. Even after accounting for the quality of laboratory procedures, research results may vary in their level of certainty and potential to guide personal action. For example, a cholesterol level obtained in a research study is likely to provide a research participant with readily interpreted information about cardiac risk (assuming that appropriate laboratory quality measures were in place), while other research results may reflect evolving knowledge that has substantial uncertainty. For example, a study might discover an association between a biomarker and a particular health risk, with an unknown effect size and no information to guide actions to reduce risk.

Most research participants, however, are unlikely to think about these threats to validity and interpretability. Hence, research results are prone to misinterpretation (e.g., confusing a research result with an established clinical test result) or misuse. As a result, it may be necessary to include a formal caveat or warning statement in return-of-results communications. Depending on the context, such statements may address

• uncertain standards,
• uncertain interpretation,
• an elevated potential for error in the result, and
• the fact that the result may not be the participant's result (e.g., in the case of a sample swap or mislabeling).

For example, appropriate disclosure to the participant might include the caveats that the level of risk is still unknown and that no actions to reduce risk are known. Researchers might also include information about plans for future research to study these questions.

Investigators are not used to identifying the full list of threats to validity, uncertainties, and caveats that are applicable to their study. In fact, incentives in both the funding application process and the research publication process minimize attention to such threats. Consequently, investigators need both guidance (e.g., a list of key questions that should be asked) and incentives (e.g., explicit consideration in IRB review) to do this task. The Multi-Regional Clinical Trials Center toolkit includes a checklist to guide IRBs and other ethics committees in reviewing plans for the return of research results (MRCT Center, 2017b).

Because people tend to assume that any test results they receive are both precise and accurate, providing information that conveys the uncertainty of the result is critical, particularly since the potential for error increases in research contexts. Furthermore, given that understanding and adjusting for uncertainty is psychologically difficult, it is reasonable to believe that, on average, the potential for over-interpretation of results and under-consideration of uncertainties is likely to be greater in practice than the reverse. The committee is already advocating for the return of results in novel circumstances, including (under certain conditions) when reliability is lower than it is for clinical results. As a result, the committee believes it is prudent to err on the side of promoting recipient attention to caveats and uncertainties. An outcome in which participants feel a need to confirm important results before acting on them would be appropriate in many situations. When a significant risk of therapeutic misconception is possible,²¹ a disclaimer distinguishing a research result from a clinical result is particularly critical.

Since clarity and concreteness are critical, caveats, cautions, or warnings that accompany the return of results need to be written in plain language. For example, many users will not understand or react to a statement that a test has “low validity.” Instead, statements should describe specific potential risks in simple terms, e.g., by making statements such as “Your result might be wrong,” “Your true results may be higher or lower than what is shown,” and “It is even possible that this result may not be yours.” Similarly, uncertainties about the meaning of the result could be stated as plainly as “We do not know what your results mean” and “We cannot recommend any actions for you to take.”

As caveats and warning statements are developed and used for the first time, they will need to be reviewed by the appropriate individuals (or groups) and tested for understanding and efficacy. Engagement with target populations is essential both for identifying which caveats are most critical to communicate and for determining the optimal methods for communication. Research has demonstrated that warnings can be used successfully to communicate benefits and risks, but only when they are specifically designed for the target audience (Andrews, 2011). Work in the environmental exposure field can offer some useful models and templates to share. The Association of Public Health Laboratories and Biomonitoring California offer models for communicating environmental exposure information to participants (Association of Public Health Laboratories, 2012; Biomonitoring California, 2018) and Biomonitoring California prototypes have undergone usability testing by Health Research for Action researchers (Health Research for Action, 2011). Additionally, FDA has explored the issue of whether and how results should be provided directly to consumers many times through the use of advisory panels or workshops that have asked experts and lay users on preferences, to explore risks of return, and develop mitigations to those risks (FDA, 2010, 2016).

Once effective warning statements are developed by investigators in a variety of fields of research, the research community would benefit from the sharing of templates and examples to avoid repeating unnecessary effort, while still allowing adaptation for a given need or context-specific communication.

CONCLUSION: Research participants may fail to understand the degree to which research results may have substantially greater uncertainties than clinical results. Little evidence exists to guide best practices for communicating warnings and qualifiers that address potential inaccuracies or potential variance in interpretation.

Identifying the Appropriate Communication Modality

Different types of communication may be appropriate in different contexts. The communication methods commonly used for returning results include

• in-person discussion,
• phone- or video-conference–based discussion,
• electronic delivery (e.g., through secure portals, including those tethered to EHRs), and
• mailing of printed materials.

Other reports have described a number of different factors that go into the selection of an appropriate communication method for returning individual research results (Fitzpatrick-Lewis et al., 2010; MRCT Center, 2017a), and the committee recommends that study teams use available guidance. For example, the Multi-Regional Clinical Trials collaborative has developed toolkits that support the return of individual as well as aggregate results and provide guidance for investigators, sponsors, and ethics review committees throughout the study life cycle from planning through study completion (MRCT Center, 2017b). As discussed above, ideally participants should be queried on their preferred communication method early in studies in which results are to be returned, and investigators should take participants' preferences into account. However, given that the potential cost, required infrastructure, and expertise will vary from study to study, the choice of how results will be communicated reflects a cost–benefit trade-off that needs to be evaluated for each study.

Delivering results in person maximizes the ability of the investigator to provide clarification, answer participant questions, and assess and address potential confusion or emotions from the participants. In some cases resources are needed to support the inclusion of specialized expertise in return, for example when genetic counselors assist an investigator in returning results to participants. As a result, this return strategy is the most time and resource intensive. Wendy Chung estimated that returning results for a large study using a team of genetic counselors cost approximately $250 per participant.²² Because of the time and resources required to plan for in-person return, this strategy is not well suited to scenarios where the results to be returned are time sensitive. Additionally, the return of results via a genetic counselor may lead to participants declining to participate due to the time commitment of counseling sessions, as was encountered by Chung and colleagues (Wynn, 2016).

The return of results via phone has many of the advantages of in-person return, including opportunities for clarification, participant questions, and addressing emotions, but it is less personal. This method can be carried out quickly if the return is time sensitive and the participant must be reached promptly. The costs associated with return by phone, like in-person delivery, remain high due to the time and expertise required.

Many patients are familiar with using electronic portals, which are commonly used for delivering clinical laboratory or other medical results (Giardina et al., 2015). These portals can be used to provide documents detailing results to participants as well as to provide links to additional educational resources. In some instances, the research results could be tethered to an existing patient portal or EHR, such as in cases where a research participant may also be a patient receiving clinical care within the institution. Although such portals typically feature a secure two-way e-mail communication option, there are a number of potential disadvantages, including a lack of opportunity for the synchronous communication of a phone or in-person return and the fact that the portal is less likely to be used by racial and ethnic minority and rural populations and those with limited health literacy or technology proficiency (Sarkar et al., 2010, 2011; Sharit et al., 2014). Furthermore, including research results in a patient's EHR may affect what is included in that patient's designed record set. Investigators in environmental health have tested other digital methods to return personalized results and engage participants in the research (Boronow et al., 2017). Establishing and using a portal has some initial and maintenance cost, but it is more easily scalable than in-person delivery, with only a marginal cost for the addition of many participants.

The return of results by mail is most useful in scenarios where researchers are returning non-urgent, reference communications and may be particularly effective for accessing individuals in remote locations, like some tribal areas where telecommunications access is limited, unreliable, or unavailable.²³ While mail is an inexpensive method for return, communication by mail has a number of shortcomings, especially a lack of opportunity for dialogue and limitations in what can be communicated in a paper-based, visual format. Certified mail can be used to help prevent sensitive participant information from being received by someone other than the participant.

Data visualization is an effective tool for helping people understand their health data (see an example in Box 5-5), and many tools have been created to assist with the development of appropriate data visualizations. For example, the Data Viz Project by Ferdio is a website that organizes visualizations by functions (e.g., comparison, part-to-whole, correlation) to make it easier to select the right visualization for a particular communication goal (Data Viz Project, 2018). Resources also are available to help in choosing the most effective type of chart (e.g., the Extreme Presentation Method; see Abela, 2018). Developed by the Risk Science Center and Center for Bioethics and Social Sciences in Medicine at the University of Michigan, Icon Array provides open-source icon arrays for communicating risk (University of Michigan Risk Science Center, 2018). Electronic Info-graphics for Community Engagement, Education, and Empowerment (EnTICE³) is open-source software that allows a user to create tailored messages and visualization outputs that are responsive to overlapping participant characteristics such as language, age, and level of health literacy (Arcia et al., 2015; Unertl et al., 2016). This software has been used during participatory design sessions to create a communication style guide tailored to inform and engage the target community. Such communications also can be used to stimulate health-motivating behaviors, for example, by offering comparisons to national rates of depression (Bevans et al., 2014) or providing dietary standards, associated risks, or recommendations for preventative action (NASEM, 2017). Under the Precision in Symptom Self-Management Center at Columbia University, EnTICE³ is being expanded beyond its original use to support biomarker result reporting including cytokines, ancestry informative markers, and genetic mutations.²⁴

BOX 5-5

Examples of Visualizations Relevant to Results Reporting.

As with any tool, visualization for returning research results must be well matched to the communication goal and data type (Arcia et al., 2013, 2018). No single visualization is ideal for all situations (Torsvik et al., 2013). Visual simplicity is also valuable, as visual embellishments (e.g., three-dimensional charts) tend to inhibit user comprehension (Tufte, 2001). A variety of authors have argued against three-dimensional graphs on both conceptual grounds (e.g., three-dimensional bars are more difficult to visually align with an axis to determine the level shown) and empirical grounds. In particular, while three-dimensional graphics may attract attention, they tend to perform worse in accuracy, which is perhaps the most critical dimension in the application to return of research test results (Fausset et al., 2008). Nor are more technologically advanced displays necessarily better: in at least some situations, interactive or animated data visualizations can be counterproductive, actually hurting an individual's ability to process the underlying data (Torsvik et al., 2013; Trevena et al., 2013; Zikmund-Fisher et al., 2012). Additionally, the Health Level Seven standard for infobuttons supports context-aware retrieval (Health Level Seven, 2018), which is increasingly being used in clinical research and can be added to a variety of electronic communication methods (portal, designated website, e-mail, etc.) to link to additional context-specific explanatory content and resources, including those that are visual or are related to the participant's specific research result (Cook et al., 2016; Torsvik et al., 2013; Trevena et al., 2013).

In many situations, a multimodal approach to returning individual results will be beneficial (e.g., delivering results via mail or electronic portal and then following up with a phone discussion or in-person meeting to offer participants a chance to ask questions and seek clarification). Consequently, health care standards that support the integration of additional sources of information into EHRs and tethered patient portals provide a foundation for multimodal approaches. Beyond infobuttons, a National Academy of Medicine Genomics and Precision Health Roundtable Action Collaborative, DIGITizE: Displaying and Integrating Genetic Information Through the EHR, has specified a set of standards including Fast Healthcare Interoperability Resources (FHIR), Substitutable Medical Applications and Reusable Technologies (SMART) on FHIR, SMART on FHIR Genomics, and Clinical Decision Support (CDS) Hooks (see Box 5-6).

BOX 5-6

Standards That Support Integration of External Resources with Electronic Health Records and Patient Portals and Are of Relevance to Return of Research Results.

CONCLUSION: Research results can be returned through a variety of communication methods that are matched to participants' needs and the context of the research results.

CONCLUSION: The appropriate use of visualizations can help achieve the communication goal for the return of research results.

CONCLUSION: Existing and emerging technical standards for the exchange of health data are available and relevant to support the return of research results at scale through electronic systems such as EHRs and secure portals.

Recommendation 10: Enable Understanding of Individual Research Results by Research Participants.

Whenever individual research results are communicated to participants, investigators and institutions should facilitate understanding of both the meaning and the limitations of the results by

A.

ensuring that there is a clear takeaway message and necessary reference information to convey what is known and not known about both the meaning of the result and potential clinical implications;

B.

communicating effectively the level of uncertainty in the result validity;

C.

providing mechanisms for participants to obtain additional information and answers to questions when appropriate and feasible;

D.

providing guidance for follow-up actions/consultations when appropriate;

E.

aligning the communication approaches to the particular needs and preferences of the participants and the context of the study;

F.

providing a written summary of the results and other information communicated to participants for future reference by participants and investigators; and

G.

leveraging existing and emerging health information technologies to enable tailored, layered, and large-scale communications when appropriate.