Ethical and Methodological Considerations for Evaluating Participant Views on Alzheimer’s and Dementia Research

Abstract

The urgent need to expand enrollment in Alzheimer’s disease and related dementia (ADRD) research has synergized calls for an empiric science of research recruitment, yet, progress in this area is hindered by challenges to measuring views toward ADRD research. This paper reports ethical and methodological considerations identified through a prospective qualitative study investigating ADRD patient and caregiver views on research recruitment and participation surrounding acute illness. Ethical and methodological considerations were identified through a combination of memoing, collaboration with a Community Advisory Board (CAB), and analysis of interview data from ADRD patients (N=3) and/or caregivers (N=28). These included risk for undue influence attributable to role ambiguity/motivational misconceptions, divergent decision-making preferences, bias contributing to low referrals of ADRD participants, and difficulty answering abstract/hypothetical questions. Many considerations were successfully addressed with multifaceted, proactive strategies and CAB input. Findings have implications for recruitment science research and the validity of inferences regarding research preferences.

Background

Alzheimer’s disease and related forms of dementia (ADRD) represent a complex, heterogeneous set of conditions characterized by progressive neurodegeneration and irreversible loses in memory, judgement, communication, and function (National Institute on Aging, 2017). Widely recognized as a national and global health priority, ADRD affects 50 million individuals worldwide, and is estimated to increase 204% by 2050 – affecting 152 million individuals (World Health Organization, 2017). Beyond those living with the condition, ADRD holds significant societal consequences – particularly for unpaid family caregivers, who provide the vast majority of hands-on care and frequently serve as proxy decision-makers for persons with ADRD. The pressing need to effectively address ADRD is amplified by the reality that there are no effective strategies for disease prevention, mitigation, or treatment. Seemingly intractable challenges in recruiting and retaining research volunteers willing to participate in ADRD studies has been identified as a major barrier toward progress in clinical and translational discoveries (Fargo, Carrillo, Weiner, Potter, & Khachaturian, 2016).

In the US alone, an estimated 70,000 participants are currently needed for clinical trials focused on ADRD, requiring researchers to screen at least 700,000 participants (Watson, Ryan, Silverberg, Cahan, & Bernard, 2014). Growing concern regarding the consequences of insufficient volunteers for ADRD research has prompted interest in establishing an empiric, applied science capable of informing best practices in ADRD research recruitment and retention. Most recently, the National Institute on Aging, a major funder for ADRD research, established a National Strategy for Research Recruitment and Participation in Alzheimer’s and Related Dementias Clinical Research as well as funding for empiric investigation of ADRD-specific research recruitment practices (National Institute on Aging, 2018). Advancing the goals of this National Strategy will necessitate broader consideration of the perspectives of persons with ADRD and those who care for them, as the end-users of research recruitment practices. Successful efforts to include persons with ADRD in research, such as the National Institute on Aging-funded Alzheimer’s Centers have recruited and maintained longitudinal cohorts of persons with ADRD since their launch in 1985. However, attention has been drawn recently to the lack of diversity and representativeness within these cohorts and the challenges of continuing to expand enrollment absent empirically-derived guidance to inform resource allocation and recruitment efforts (Gilmore-Bykovskyi et al., 2019a; Gleason et al., 2019).

Despite successful inclusion of persons living with ADRD in some health-related research, many studies indicate that persons living with ADRD are frequently excluded from research studies and little is known about their priorities and values regarding research, or recruitment and engagement preferences (Beattie, Daker-White, Gilliard, & Means, 2004; Gilmore-Bykovskyi et al., 2019a; Hellström, Nolan, Nordenfelt, & Lundh, 2007; Novek & Wilkinson, 2019; Whitfield & Wismer, 2006). Advocacy organizations have called for more deliberate inclusion and engagement of persons living with ADRD and their caregivers in research in response to long-standing ethical concerns that persons with ADRD are excluded from decision-making about their own research and care (Dementia Action Alliance, 2015; Gitlin, 2018; Wilkinson, 2002). Arguably, this exclusion violates common values of social responsibility (Barnes & Brannelly, 2008), whereby guiding practices used in ADRD research are developed without input and representation from those who are the ultimate recipients of these practices, and whose values may differ substantially from non-cognitively vulnerable members of society.

The reality that most persons with ADRD at present are unlikely to benefit from current research advances within their lifetime highlights the potential that their preferences and perspectives around research experiences may diverge from the priorities and goals of scientists and funders. We contend that further progress in this line of inquiry is hindered by lack of understanding of ethical and methodological complexities inherent in empiric investigation of ADRD and caregiver participant views and preferences regarding research recruitment practices. Ethical challenges to addressing research access for persons with ADRD with regard to decision-making and informed consent have been addressed in prior work, including the role of caregivers as proxy-decision makers (Black, Wechsler, & Fogarty, 2013; Kim, Karlawish, & Caine, 2002). However, little is known about challenges specific to uncovering the values that shape participants feelings toward practices in the research recruitment process, or how they may shape decision-making around participation. Consequentially, our understanding regarding how persons with ADRD and their caregivers understand, interpret, and prioritize research participation is limited. Addressing this line of inquiry requires focused efforts to identify and examine the perspectives of persons with ADRD and their caregivers on research and recruitment to an extent that has previously been under-addressed. In this project, we focused on determining and classifying specific ethical and methodological considerations, and potential solutions that arose through attempts to empirically investigate the perspectives of persons with ADRD and family caregivers regarding ADRD research recruitment and decision-making around participation.

We conducted in depth semi-structured qualitative interviews with people with ADRD and caregivers surrounding acute illness care episodes to understand their perspectives and preferences regarding research recruitment. Because persons with ADRD frequently enter acute illness care settings, they represent an important component of the care continuum and opportunity to identify and engage potential research participants (Gilmore-Bykovskyi, Block, Mullen, & Thomas, 2019b; Phelan, Borson, Grothaus, Balch, & Larson, 2012). We report on how participants interpreted and imagined ADRD research studies and invitations to participate (recruitment practices), describe the specific ethical and methodological considerations encountered throughout the study, and detail solutions implemented in response to these considerations.

Methods

Ethical Approval

All procedures performed in studies involving human participants received approval from the Institutional Review Board (IRB) at the University of Wisconsin-Madison. Written consent was waived; instead, we obtained verbal informed consent from all participants. As required by IRB guidelines, a fact sheet including all the information provided during consent was also provided to participants.

Participants

Participants included family caregivers for people with ADRD and individuals with a diagnosis of ADRD. Eligibility criteria for family caregivers included at least monthly, unpaid care or support for a family or friend with ADRD. Caregivers were eligible to participate whether or not the person with ADRD participated. Eligibility criteria for people with ADRD included presence of pre-existing diagnosis of ADRD and determination of capacity to consent to research. Diagnosis of ADRD was determined by clinical staff, and determination of capacity to consent was guided using previously established methods for minimal risk research with people with ADRD (Holden et al., 2018). Finally, eligibility criteria included the ability to participate in interviews in English. For situations where the person with ADRD demonstrated decisional capacity, and their caregiver was also interested in participating, participants had the option to choose to complete an interview individually or as a dyad.

Recruitment and Consent Procedures

Potential participants were recruited through a previously developed multimodal recruitment strategy tailored to the acute illness care context, which involved referrals from medical or surgical units through transitional care services, or the emergency department (Gilmore-Bykovskyi et al., 2019b). The recruitment process involved identifying optimal post-decisional timeframes in which to approach potential participants and/or caregivers regarding the research opportunity. The research team answered participant questions regarding the study, screened to confirm eligibility, obtained verbal informed consent, enrolled participants in the study, and completed interviews.

After study procedures, benefits, and risks were described, participants were asked to restate study procedures to confirm capacity to consent, informed by Resnick and colleagues Evaluation to Sign Consent Form (Resnick et al., 2007). Because cognition regularly fluctuates among persons with ADRD, interviewers were attentive for indications of uncertainty or confusion throughout the interview process that would indicate lack of understanding regarding the voluntary nature or risks of the study.

Interview Procedures and Analysis

Interviews followed a semi-structured interview guide which focused on briefly addressing participants’ journey with ADRD to establish rapport, and transitioned to exploring views and feelings toward ADRD research, preferences regarding research recruitment, and decision-making regarding participation. Each interview was conducted by one of two research team members with training in qualitative methodology and expertise in dementia care. The majority of interviews took place following the acute illness care episode, most often in the participants’ home or at a private meeting room in a community library, at a time that was convenient to the participant. Five participants elected to complete interviews while they were still in the acute illness care setting.

Identification of Ethical and Methodological Considerations

Several methods were applied to identify and address ethical and methodological considerations. First, ongoing team dialogue and memoing was employed throughout the research process (Birks, Chapman, & Francis, 2008). This involved the research team meeting following interviews to share and discuss observations about considerations that arose in addition to detailed memos recorded following recruitment interactions and interviews. These memos included information on the identified consideration, the primary people involved, ethical sequela, implications for obtaining accurate perspectives regarding ADRD research participation, and potential strategies to alleviate these considerations. To address considerations specific to interviewing methods or style, we also engaged ongoing input from a lay Community Advisory Board (CAB) to ensure clarity of interview questions and to improve tools for use during recruitment in an acute illness care setting. Lastly, thematic analysis of completed interviews was performed to further review and document sources of methodological considerations specifically (Braun & Clarke, 2006).

Throughout the process of memoing, the research team regularly consulted with clinical recruitment partners and a lay CAB to gauge their perspectives on identified considerations and strategies. The CAB consulted on language and presentation of study materials in attempts to address challenges regarding interpretation of the goals of research in recruitment scenarios and situations investigated. The CAB consists of members from community center programs, and their role is to provide feedback on supplementary materials used throughout interviews to make them clearer and more engaging. Solutions and strategies implemented in response to specific considerations encountered were designed with input from the CAB, as well as recruitment partners as appropriate. These included the development of visual cards illustrating recruitment steps [Supplementary Material 1], a visual questionnaire guide to use while asking questions regarding attitudes towards ADRD research [Supplementary Material 2], and development of video that illustrated recruitment into an ADRD study in an acute care setting for participants to respond to during the interview.

The process of memoing was complemented with a systematic review of interview transcripts using a thematic analysis approach outlined by Braun and Clarke to identify thematic sources of the ethical, methodological, and practical considerations of conducting the interviews (Braun & Clarke, 2006). Interviews were audio recorded and analyzed using NVivo qualitative data analysis software. Thematic saturation was reached after 25 participants had been interviewed. A further six participants were interviewed to confirm data saturation across major findings and sufficiently evaluate the utility of CAB-informed solutions to improve the quality of data collection during interviews. Following initial review of all interviews, the study team developed a data-driven coding framework related to challenges in obtaining valid data on participant’s perspectives regarding research participation. The coding framework was iteratively reviewed in conjunction with supporting interview data with other members of the interdisciplinary study team. This review first emphasized an inductive approach, wherein study team members confirmed consistency of individual codes with interview data and critically examined the coherence and precision of individual codes (Braun & Clarke, 2006). Three authors independently coded the interviews line-by-line in NVivo. Using an iterative process, we reviewed codes, identified emerging themes, and resolved discrepancies through consensus (Braun & Clarke, 2006). To ensure coding was comprehensive, all interviews were reviewed in their entirety, often more than once. After all transcripts were coded, the research team reviewed and discussed major themes (Table 1). Inter-coder agreement was reviewed throughout coding to identify codes with low agreement or where re-training was needed. Inter-rater reliability was moderate with a percent agreement range between 86.2% and 99.1%. Coding comparisons were run weekly during the early stages of coding. The nature and frequency of variation in coding was documented in a log by each coder and discussed in meetings held weekly. Reliability increased after these meetings. To evaluate the usefulness of supplemental interview materials developed with input from the CAB in response to identified challenges, we specifically examined the frequency of codes indicating participant uncertainty with interview questions. (Table 1).

Table 1.

Coding Framework Applied to Interview Data from Patients with Dementia and Caregivers regarding Research Recruitment

Code	Definition of Code	Sample Quotes
Participant responses indicating difficulty understanding question	Participant explicitly states questions are not clear or difficult to answer or explicitly asks for clarification, describes questions as unclear or that question is frustrating or challenging.	Interviewer: “When you make a decision to yes participate in a research study, do you consult with anyone else?” Caregiver: “I don’t think I understand the question.”
		Interviewer: “So my last questions are really just about how we can get people more interested in research studies perhaps people who are more hesitant, what can researchers do better?” Caregiver: “Well, I have to think about that that’s a tough question”
		Interviewer: “How could researchers reach out to people better?” Caregiver: “That’s a good question. How could they? I’ve seen ads in the paper, um can you google studies? I don’t know.”
Participant responds with information unrelated to the question	Participant responds to question in a way that does not relate in content or topic to the question at hand, typically responding with an anecdote or story tangential to the question	Interviewer: “Great. When you are invited to participate in research studies, is there a certain way you’d like to be asked to participate in the research study?” Caregiver: “Well I don’t know really what you’re kind of getting at. Let me tell you this: I’m a basic researcher. What you’re getting at is introspective data, and introspective data is not the easiest kind of thing to deal with. And I like to deal with, I have my students and I like to deal with facts, academic testing and so on and what you get off the idea where you can kind of nail something down and that it won’t change from one day to the next.”
		Interviewer: “I noticed you said this type of study is extremely important when we started. How do you feel about it compared to these other types of studies? Do you think this one is more or less important?” Caregiver: “Well for myself, I would be more interested in, you know. Say for instance, I used to work in oncology. I saw what my patients do and how can we improve the quality, you know, lessen the quantity and improve the effectiveness of these medications for these people…and it costs so much, you know. I don’t agree that it should cost so much. I saw people lose their cars and their homes and they ran out of money and lost their lives. And I am completely disagreeable that they should have to lose their lives because they don’t have any money to pay for their medications.”
Interviewer providing additional definitions, prompts, examples to help participant answer question	Interviewer provides definitions of research concepts for the participant so that they can answer the questions at hand, restates question more than once, or uses additional questions and detail to build on the original question	Interviewer: “Before this conversation, have you ever participated in this type of study?” Caregiver: “So when you say this type?” Interviewer: “So, a study that is short in duration and just involves kind of talking about your experiences with someone.” Caregiver: “Oh. Yeah just that study I did in November or December.”
		Interviewer: “If you or the person you care for were invited are there things researchers should be aware of particularly being in a hospital?” Caregiver: “Now are you talking about the person in the hospital, the person with dementia?” Interviewer: “Yes, let’s think about that; let’s say we want to invite a caregiver to participate in the study or perhaps a caregiver who made decisions about the patient with dementia if the person with dementia. What things should researchers be aware of about that timing about being in the hospital and the other things that are different or have sensitivities to?” Caregiver: “Let me give you an example he has been in the hospital in the area when he had the event it is really tough because they are in an environment that they are not familiar with because some things that they have to give him to calm him or kind of like a sedative he had a problem with that he was very agitated and that was tough because he wanted to be up and down all night and I don’t know how to quite answer that I guess”
Participant responses to question indicates role ambiguity	Participant statements indicating difficulty distinguish between clinical and research staff, or demonstrated a lack of distinction or understanding between clinical and research staff	Interviewer: “Do you think others that you might know who have medical experience would be able to distinguish nursing staff from the research staff?” Caregiver: “I don’t think they’d understand the difference.
		Interviewer: “Is there anything you think that researchers should do differently compared to primary doctors or nurses when they’re approaching you?” Caregiver: “Yeah I couldn’t really tell who researchers were and who were doctors I was mainly focused on you know who the primary caregivers were. You know in order from doctors to nurses to nurses assistants to social workers. Just understand the construct of the people who were charged with you know monitoring my dad’s situation. I didn’t really distinguish, there might have been researchers there. I don’t remember any significant interaction with any of them. Like I was introduced to people who just seemed to be, you know I didn’t find out their roles so maybe they were researchers I don’t know.”
Participant response to question indicates potential motivational misconception regarding purpose of research study	Participant motivations for participating in research reflect potential misunderstanding of the purpose and goals of research, such as thinking research will be personally beneficial	Caregiver: “I guess our motivation all along has been strong in maybe they can find something that will help us and maybe we could do something that will help them.”
		Interviewer: “How would you go about making the decision with or for your mom about potential participation in a medication study related to her care?” Caregiver: “I think it would be something that we would consider but in most cases it has something to pertain to her overall well-being because in the short run because she probably doesn’t have a lot of long term left. I probably wouldn’t consider it unless it was something that may change her current status of dementia to something more positive.”
Participant describes decision-making process for research participation	Participant descriptions of their process of making research participation decisions, including factors they weigh and the degree/nature of involvement of others in making decisions	Interviewer: “Let’s say your mom is in the hospital and you’re not there at the moment do you think this would work for someone like her?” Caregiver: “It would be harder for her um she probably would be confused about the whole thing and I think she probably would hesitate to get involved just in much of everything you know if she doesn’t have to do it she probably wouldn’t do it so I just don’t think there’s really an approach that would get her interested I think actually having a caregiver there might help.”
		Interviewer: “Is there any certain way you want a researcher to introduce themselves or distinguish themselves?” Caregiver: “So I would say if [Person with dementia] is going to be involved in a study, when it’s asked and introduced to her I would want to be there. I wouldn’t need to be there for the study because then I know that she knows what’s going on.” Interviewer: “Yeah that makes sense. And then let’s say that you’re making that decision, yes it sounds like a good idea, what would that decision making process look like between you and your mom?” Caregiver: “Basically what I usually do whether it’s a medical professional or whatever, they explain what they’re going to be doing, I regurgitate it again, either in my words or the same words again and say so you know they’re going to be doing this. Oh yeah I’m not stupid. It’s like ok good. I just want to make sure you’re aware. So usually that’s our dynamic.”
		Interviewer: “Would you, how would you feel about researchers approaching your mom when you’re not there?” Caregiver: “Well, you know it was given that she has dementia?” Interviewer: “I do.” Caregiver: “I mean if she didn’t have dementia I wouldn’t care at all it’s her decision. Now it’s to the point where she’s not going to remember anything they said anyway. But given where she is I don’t’ think people should be coming in and talking to her without me knowing about it.”
		Caregiver: “The thing that motivated us to participate in research was really the possibility that it would actually be helpful for us. And I have no idea whether it would delay the process or not but that was really what drove us.”

Findings

Collectively 91 potentially eligible participants were referred to the study team. Of these, 31 were eligible and completed an interview, which averaged 44 minutes in length (range 23 to 100 minutes). Among the 67 participants (people with ADRD and caregivers) referred but not enrolled, 31 were lost due to challenges making phone contact within the limited number of attempts allowed per study protocol, 30 were lost due to challenges making contact with the activated power of attorney in the acute illness care setting, three were discharged prior to first contact by the research team, and three declined to participate. In general, this rate enrollment rate is common in ADRD and acute illness care-based studies (Apostolova et al., 2017; Nicks et al., 2017).

Of the 31 interviewees, 25 were caregivers who participated in individual interviews, and three were conducted with dyads of caregivers and people with ADRD. All caregivers were asked if they would like information on support for caregiving in their area. If so, they were provided a list of support resources, contact information, and summaries of the resources. Demographic characteristics of participants are described in Table 2.

Table 2.

Demographics of Interview Participants (N=31)

Age (years)
Mean	63
Range	23–92
<70	15 (49%)
70 to 75	6 (19%)
76 to 80	4 (13%)
>80	3 (10%)
No Response	3 (10%)
Gender
Female	21 (68%)
Male	8 (26%)
No Response	2 (6%)
Ethnicity
Black or African American	1 (3%)
Hispanic or Latino Ethnicity	1 (3%)
Native American	1 (3%)
White	28 (91%)
No Response	0 (0%)
Education level
High School Diploma or Equivalent	2 (6%)
Technical School, Vocational Training, Community College	3 (10%)
Some College	1 (3%)
4-Year College	9 (30%)
Post College	12 (38%)
No Response	4 (13%)
Employment Status
Full-Time	7 (23%)
Part-Time	3 (10%)
Not Working	1 (3%)
Retired	16 (51%)
No Response	3 (10%)
Relation to Care Recipient
Spouse	13 (42%)
Parent	10 (32%)
Other Relative	3 (10%)
Friend	3 (10%)
No Response	2 (6%)

Throughout the study, we identified specific ethical considerations – some with practical implications in relation to recruitment and participation of persons with ADRD, and others with direct methodological implications for drawing valid inferences regarding views on research. The most salient ethical considerations identified were: risk of undue influence either through ambiguity regarding researchers’ roles and/or through participants’ motivational misconceptions regarding ADRD research; divergent preferences for decision-making processes during study recruitment; sources of bias that produced under-inclusion of people with ADRD; and uncertainty experienced by participants attributable to difficulty addressing the abstract/hypothetical nature of research participation and decision-making.

Risk of Undue Influence Due to Role Ambiguity and Motivational Misconception

In the recruitment process, we identified a risk for potential undue influence due to a lack of distinction between research and clinical care, along with confusion regarding the goals of research. Role ambiguity between clinical staff and researchers was identified as having implications for risk of undue influence, even if unintended, as people might feel study participation would be linked to clinical care or may improve relationships with the clinical entity or staff. Consequentially, absent an observant recruiter, a participant could potentially participate in a study feeling it is part or extension of their clinical care, rather than optional research.

Role Ambiguity

Perhaps the most salient ethical challenge encountered in our attempts to obtain data on views of people with ADRD and caregivers regarding research was the fact that very few participants readily distinguished between the roles of clinical staff and researchers, regardless of previous exposure to research. This finding was both observed by the team through clarifications that were needed during the recruitment and consent process; and was also evident in analysis of interview data (Table 1). Though no participant named “role ambiguity” explicitly as a challenge, several caregivers reported a common phenomenon of having difficulty keeping track of names, faces, and roles:

“There are so many people that come in with clipboards for materials to be signed. Social workers. Medical people that need signatures and at that point in time when you came you were just one more group of medical people.”

-Caregiver

For example, caregivers stated they could not readily differentiate between researchers and doctors, instead focusing on who the people were that were primarily responsible for the patient’s care:

“Yeah I couldn’t really tell who researchers were and who were doctors I was mainly focused on you know the caregivers wanted to know who the primary caregiver were.

Caregiver

Motivational Misconceptions in Research

Partially influenced by role ambiguity, participants’ motivations for participation may not have been aligned with the purpose and risk to benefit ratio of the study, as the study had no direct benefits Half of the participants appeared to have difficulty separating the goals of research (to generate generalizable knowledge) from clinical care (to benefit an individual person). This finding was apparent when examining code interview data as participants frequently commented on the potential to benefit the person with ADRD, or for caregivers to learn more about the condition:

“My primary motivation was that surely since they were doing research maybe they could help slow the process down or give medication that would work or at least be in care of people who knew what they were doing… and well maybe it could bring us some hope”

-Caregiver

Participants also shared that the lack of curative treatment for ADRD drove them to seek opportunities that offered some sense of hope. Almost all participants shared that they felt research participation is key to discovering ways to slow and treat ADRD:

“And if it hadn’t worked, I mean you guys don’t know until you try. And you can’t try if you don’t have willing participants … I love life, and I am going to do anything I can to hang on to it.”

-Caregiver

A potential consequence of these motivational misconceptions is that participants may become disillusioned with research when immediate improvements related to symptoms of progression are not realized. Additionally, these motivational misconceptions were linked to potential undue influence for research participation, which was observed even when information presented about research did not support the notion that the goal of research is for personal benefit. This phenomena has clear methodological implications for efforts to interpret data regarding motivations for research participation in the event that those motivations are contingent upon fundamentally different interpretations of the concept of the research purpose.

Divergent Decision-Making Processes during Study Recruitment

For this study, people with ADRD were unable to participate directly if they had an activated legally authorized representative responsible for decision-making, most often an activated health care power of attorney, meaning two independent physicians determined the person with ADRD to lack decisional capacity. These criteria reflect common institutional policies and research practices, wherein people with ADRD with an activated, legally authorized representative are designated as no longer being able to provide informed consent for research studies, but may provide assent to participate in research. However, in recruiting people with ADRD and caregivers, we encountered situations where participant and familial processes for decision making about research participation were divergent from these procedures. Generally, participants did not view the legally authorized decision maker as the most appropriate first step in the invitation or decision process. We observed situations wherein families demonstrated distributed and shared decision-making structures. These family decision-making processes were highly individualized to the situation often with involvement of the person with ADRD. In response to a question about involving family members in the decision for a person with ADRD to participate in research, a caregiver stated:

“I am the primary decision-maker, but I would certainly ask. I would ask and say “what do you think?” I would certainly consult with the rest of the family. Because of the fact that I probably wouldn’t think of every consequence of my decision…”

-Caregiver

Caregivers felt the person with ADRD should be involved in research, and that the caregivers’ role in the process should be largely determined by the person with ADRD’s needs and preferences. The majority of caregivers emphasized that their family member with ADRD retained the ability to invite or deny conversation, and that this could be extended to engagement with researchers:

“I mean she can have those conversations very easily … I like being there at times to advocate for her and once in a while make a little correction. So those are the modifications that once in a while it’s like we have to let you know what the whole story is. Because she’ll answer honestly, which she should.”

-Caregiver

This finding demonstrates that caregivers felt compelled to not only include people with ADRD in research and shape decisions on research participation based on the person with ADRD and other family members’ perspectives and preferences. This finding calls to question whether institutional policies guiding study procedures appropriately prioritize individual proxy informant decision-making rather than facilitating processes for more inclusive decision-making.

Role of Relationship-Building in Deciding to Participate

Throughout study recruitment and in response to questions about their views on recruitment, participants noted ways positive relational qualities with the researcher may encourage participation. Caregiver participants also shared the importance of research staff to be “thoughtful,” “kind,” “knowledgeable,” and “attuned to the person’s feelings.” Participants consistently described these preferred researcher attributes as facilitators towards their interest and subsequent engagement. This was further evidenced by several participants preferring to have ongoing contact in subsequent phases with the same research staff who initially invited them to join the study, often remembering names or characteristics of the person they initial met with.

However, it was also evident that relationship building during a recruitment process implemented within an acute illness care context is challenging due to the environmental limitations and time constraints. It was not feasible for every participant interaction to provide sufficient time for dialogue and other non-verbal communication necessary to begin to establish an authentic relationship. It is possible that this may have contributed, in part, to lack of retention or differentially influenced motivational factors and views toward participation.

Sources of Bias Resulting in Low Referrals of Persons with ADRD

During the recruitment process, we recognized that clinical recruitment partners referred practically no persons with ADRD to the study team despite our efforts to support their inclusion. Originally, our efforts to promote inclusion of people with ADRD and decisional capacity included offering dyadic interviews with caregivers and using verbal instead of written consent.

Conversations with study partners and review of referral documentation revealed bias toward selecting participants perceived as more willing and able to participate in research or easier to converse with. These biases have potential to contribute to systematic under-inclusion of persons with ADRD in research, perpetuating unequal distribution of access to its benefits and burdens. It is possible that the nature of this study exacerbated these biases due to the requirement of participants to arrange an interview and discuss their perceptions with the study team.

Abstract or Hypothetical Nature of Research Participation

Given the concepts of research are not well-defined or commonly used within the lay community, almost all participants had difficulty relating to questions about research recruitment practices, often needing clarification of the questions. This resulted in methodological challenges in obtaining relevant and valid data, as confirmed via examination of interview data. Specifically, hypothetical questions such as “what comes to your mind when you hear the word research?” or “what comes to mind when you hear the phrase research on changes in memory?” were challenging. In response, many participants resorted to describing their experiences as a caregiver or person with ADRD and did not directly answer the question. To facilitate methodological comparison between hypothetical and experiential questions, we also solicited input on prior and past experiences, although many participants gave short, vague answers, typically stating the experience was good.

For a subset of participants, the hypothetical nature of the questions also created uncertainty and frustration with what interviewers were looking for in an answer. In response to a question asking what the participant would like to know before participating in an ADRD research study, a participant responded:

“I don’t know to be honest with you. I’m not really sure what you’re rooting at there. I mean, are you hoping to figure out how to treat these changes or are you hoping to spot them early on? I’m not sure what your aim is here. Are we picking up on cues that would cue you to changes? I’m not really sure what you’re asking me.”

– Person Living with Dementia

At times, participants apologized to the interviewer for not understanding. In response to a question about the proper timing a researcher should approach a person with ADRD in an acute illness care setting, a caregiver responded:

“I think nighttime is hard for him because they don’t know where they are. I don’t know if I answered that very well or not I’m sorry.”

– Caregiver

The most common source of frustration stemmed from uncertainty on how to answer the questions. One caregiver stated that they had a problem with broad questions: “I have trouble personally with broad questions. I have trouble you know are we talking universally, you know so depending on what you’re after.” Collectively, there were concerns that difficulty responding to study questions about past research experiences or hypothetical scenarios to obtain insight into preferences introduced a risk of placing an undue burden on study participants and had implications for the validity of inferences drawn from data with high degrees of uncertainty.

Strategies for Acute Care Recruitment of People with ADRD

Role Ambiguity

To counteract the effects of role ambiguity and minimize this risk, all research staff wore a name badge that identified them as a university employee, not acute illness care staff and removed any badges that were similar in branding or style to the acute illness care badge. A standardized introduction script was developed with input from a CAB, which helped the study team engage language that made the distinction between care and research more explicit. Potential participants were also offered the opportunity to follow-up and consent to the research after discharge from the acute illness care setting to signal a separation from the clinical setting and care. Our informed consent document and script also emphasized that participation in and withdrawal from the research study has no impact on care received during acute illness care. Review of interview data suggest that while these steps may help to reduce uncertainty, some participants may have preexisting impressions of dual roles between clinicians and researchers that may require ongoing clarification to mitigate any risk of undue influence.

Motivational Misconceptions in Research

We first investigated participant’s understanding of the concept of research prior to further questioning motivations driving participation. We endeavored to do this by incorporating a study question: “What does the word research mean to you?” We considered the ethical implications of some participant’s motivations to participate in research, such as thinking research can be used in delaying the process of dementia.

After investigating participants’ working definitions for research, we ensured the study team further clarified information stating that the study offered no direct benefits for caregivers or people with ADRD and made sure to re-explain the research study purpose and benefit-to-risk ratio at the time of participation. Interestingly, despite this clarification participants still frequently referenced personal benefit as a motivation for participating in research in interviews.

Sixteen participants withdrew from the study during this clarification, with some stating that they were no longer interested after hearing the study details again and some declining due to other life events or stating they did not have time. This rate of withdrawal illustrates the importance of clearly stating the study purpose and lack of direct benefits in order to reduce the risk for potential undue influence due to motivational misconceptions.

Decision-Making Processes

The study team implemented adaptations to study procedures that were more responsive to family preferences around decision-making and maximize involvement of the person with ADRD, while remaining adherent to protocols regarding decisional capacity and informed consent. Namely, we emphasized including the person with ADRD in the conversation by speaking to them along with the caregiver, rather than speaking about them in their presence, even if they themselves could not be recruited into the study due to lack of decisional capacity. When more than one caregiver was present in the room, we framed information about the study and participation broadly, inviting both caregivers to participate in the study if appropriate. This change also responded to the fact that legally authorized representatives were not always the closest relative or friend to the person with ADRD. Lastly, we modified our approach to offer time to consult with other important decision-makers prior to making a decision about participating in the study, most often by offering to step out of the room while they considered.

Under-Referral of Persons with ADRD

To address the under-referral of persons with ADRD, the principal investigator presented information on the heterogeneous nature of abilities, strengths, and limitations experienced by persons with ADRD to each clinical recruitment partner. This presentation referenced empiric evidence and emphasized the consequences of exclusion of persons with ADRD and highlighted data demonstrating the decisional abilities of persons at earlier disease stages, as well as the unique first-hand perspective of persons with ADRD on their own research.

Following these discussions, the study team received more referrals for persons with ADRD, though consent rates for these participants remained low. Collectively, 11 people with ADRD were referred to the study team, three of whom completed interviews (two dyadically and one independently). Requests for a dyadic interview originated from the people with ADRD, and not the caregivers. Of the eight people with ADRD who were not successfully recruited, three were discharged from acute illness care before the research team could make initial contact and five received the maximum number of phone calls permitted by our protocol with no follow-up. The reasons for attrition did not differ from reasons for attrition of caregiver participants.

Strategies to Improve Relationship-Building

We attempted to mitigate the challenges of building a relationship with participants in an acute illness care setting using a number of strategies. First, the study team worked with nursing staff to determine the most appropriate time for the study team to approach the person with ADRD, to anticipate and minimize disruptions during initial conversations. We also confirmed whether caregivers were present in the room with the person with ADRD, and if the person with ADRD had decisional capacity, or had a legally authorized representative (proxy) decision maker. This ensured that person with ADRD and their caregivers would be willing and able to discuss the study before approaching. When recruitment was interrupted, the study team provided fliers to prospective participants and included study details as well as contact information for the study team. These fliers also served to reduce any perceived time-pressure to accept the invitation to participate.

Data Collection Material Revisions

To improve our ability to collect relevant data and mitigate uncertainty during the interview procedures, we undertook a collaborative revision process of all study materials consisting of two phases with a lay CAB (Figure 1). Additionally, we created a list of phrases for interviewers to use before and after questions to acknowledge the difficulty of certain questions and allow participants to skip or come back to other questions, including, “I know it can be challenging to think of examples sometimes, would you like to come back to this question?” and, “Sometimes this question can be challenging for people, let me know if you prefer to skip it.”

Figure 1.

Phases of revisions to study materials for interviews with patients with dementia and their caregivers.

The original study materials and interview questions consisted of an interview guide with general questions on the caregiver or person with ADRD’s preferences around research and recruitment approaches. The initial interview questions were challenging for participants to answer, as evidenced by heavy prompting and redirection on the part of the interviewer. Hypothetical questions were determined to be particularly difficult and frustrating for participants. Five participants were interviewed using these original study materials, and participants stated uncertainty with the interview questions an average of four times per interview.

The first set of supplementary interview materials, as recommended by CAB members, included incorporation of visual tools to use in coordination with targeted questions. The first visual tool depicted common types of specific procedures within ADRD research, to be used in conjunction with questions to gauge the participant’s preferences around recruitment into a study. The procedures included blood draws, magnetic resonance imaging scans, lumbar puncture, medication administration, and qualitative interviews. The second visual tool depicted key recruitment steps along with questions on the appropriateness of the steps, their order, and whether anything was missing. We reduced the number of hypothetical questions we asked, asking questions that were scenario-based through the visuals. Sixteen participants were interviewed using these revised study materials, and participants stated uncertainty an average of 1.5 times per interview.

In the second phase of revisions, we developed, filmed, and incorporated a scenario-based video that play-acted the recruitment steps within acute illness care. The characters included a patient with dementia, family member, nurse, and study recruiter. The video was segmented into chapters, with questions to accompany each chapter and gauge the participant’s perspectives on the recruitment steps depicted. The use of a video further allowed us to ask specific questions on abstract concepts such as “researcher approach.” Six participants were interviewed using the scenario-based video, and participants stated uncertainty or confusion with the interview an average of 0 times per interview.

Discussion

This study provides novel and valuable insights into ethical and methodological considerations that arose in investigating participant perspectives and preferences regarding ADRD research recruitment and participation. Collectively, these findings suggest that interview studies conducted with caregivers and persons with ADRD about research recruitment and participation may be subject to biases and/or misconceptions on the part of study partners or participants. These biases and misconceptions have ethical consequences for how well-informed decisions about research participation are, for who has access and is included, and for how questions about research recruitment practices may be answered differentially based upon various beliefs and misconceptions about ADRD research. These findings shed light on the multiple sources of bias and misconceptions that may make reliance on prior decisions or hypothetical scenarios regarding research participation frustrating to answer for participants, and potentially invalid, as they may be based upon fundamentally different belief systems and understandings about research. While the current findings are specific to the context of ADRD research recruitment surrounding acute illness episodes, the nature of sources of uncertainty are likely applicable beyond this context – providing a useful, albeit preliminary, understanding of consequential ethical and methodological considerations in empiric investigations in applied recruitment science research.

In the present investigation, the study team was able to successfully mitigate most considerations that arose, but this was only possible due to the proactive and deliberate plan to identify these considerations. Provided the very limited evidence base in this area (Gilmore-Bykovskyi et al., 2019b), this finding in and of itself lends support to the use of proactive methodological strategies for identifying other ethical, methodological, and practical considerations that may arise in other contexts as they may vary based upon the nature of the study questions and methods. Absent incorporation of those procedures, the underlying sources of some challenges such as frustration in investigating the hypothetical nature of participation may have been written off as “lack of awareness” or “lack of knowledge” on the part of study participants. The strategies engaged also demonstrate the utility of close partnership with lay individuals – in this case through a lay CAB – to help the study team bridge communication and belief-system differences, and fully understand the nature of misconceptions that arose and developing revised approaches for mitigation and clarification.

The acute illness care setting had a number of specific challenges during the recruitment phase, especially in regards to role ambiguity and being respectful of the various decision-making processes of the participants. Once participants were enrolled, the challenges were generalizable to a typical qualitative interview study, such as challenging interview questions.

A notable methodological challenge we found amongst caregiver and ADRD participants was the difficulty participants had responding to questions about hypothetical or abstract questions, with ethical consequences related to undue uncertainty when attempting to answer.. This is of particular concern when wanting to include persons with cognitive impairment in research, as they may have greater difficulty with hypothetical questions.

Hypothetical questions are heavily relied on in recruitment science to gauge willingness to participate in research studies or biobanks (Darnell, McGuire, & Danner, 2011; Hooper et al., 2013; Richards, Ross, Robens, & Borglin, 2014; Zhou et al., 2017). Previous research has found such hypothetical questions to be difficult to answer and even contradictory to the participant’s actual behavior (FeldmanHall et al., 2012; Fitzsimons & Shiv, 2001; Johnsson et al., 2010; Pardo, Midden, & Miller, 2002). FeldmanHall et al. (2012) finds that adding context to a question can bring hypothetical choices more in-line with behavior (FeldmanHall et al., 2012). In our case, context was enriched using a video showcasing recruitment steps in a simulated hospital environment.

Prior work has found that participants facing subjective cognitive complaints had similar difficulty particularly with items requiring personal or technical information participants may not know or remember and questions that evoke emotional responses (Hill et al., 2019). Asking participants to reflect on past experiences that they may have forgotten has a high potential to introduce bias (Hill et al., 2019). Proactive and deliberate plans to address these considerations is imperative to reduce negative emotions and bias. Specifically, incorporation of more situationally-specific audiovisual tools to complement interviews helped to reduce this bias, and improve consistency regarding the nature of inferences drawn from study findings.

We also identified the potential risk of undue influence that resulted from motivational misconceptions regarding the purpose of research. Along with interview findings, we found that 16 out of the 91 participants approached refused to participate if participants truly understood the lack of personal benefit. The context of recruiting through acute care may have increased motivational misconceptions, as participants were less likely to distinguish between researcher and clinical staff. It is unclear if this finding is so salient in the context of ADRD due to the lack of effective therapies and treatment, or if this may apply to other contexts as well. While our participants demonstrated an understanding of double-blinded studies and the use of placebos, there was still a belief that they purposely will receive the treatment most likely to benefit the person. This view is in concordance with findings suggesting that proxy-decision makers typically decided for the person with ADRD to join a research study based on what they believed would maximize the person’s well-being (Karlawish et al., 2008; Sugarman, Cain, Wallace, & Welsh-Bohmer, 2001).

The term for this hope that decisions about one’s personal medical care are being made for one’s benefit while a participant in a research study has been defined as therapeutic misconception, which relates to our findings of motivational misconception (Appelbaum, Roth, Lidz, Benson, & Winslade, 1987; McCormick, 2018). If a person believes their participation will provide them with access to treatment, their consent – no matter how freely offered – would be misinformed. Clear separation between treatment and research must be maintained and articulated to participants (Grieselhuber, Kodner, Brown, & Yu, 2017).

While therapeutic misconception exists as an ethical challenge across the spectrum of clinical research, it can be heightened in research involving subjects with consent capacity impairments. A conceptual basis formulated by Lidz et al. finds that therapeutic misconception is not the result of inadequate disclosure or participant incompetence rather it stems from divergent cognitive frames (Lidz et al., 2015). The researchers’ frame places the clinical trial in the context of scientific designs for assessing intervention efficacy, whereas the participants’ cognitive frame that is personal and focused primarily on their own or the people in their networks’ medical problems (Lidz et al., 2015). There has been minimal work specifically examining therapeutic misconception in the context of ADRD research. Dunn & Palmer have brought attention to this gap, stating that the limitations in number and effectiveness of available therapeutic agents for ADRD could make persons with ADRD or their decision-makers particularly susceptible to therapeutic misconception (Dunn & Palmer, 2017). Another study found that the reasons proxies offered for enrolling patients in research was driven mostly by hope for direct benefit to the person with ADRD, the perception that there is no treatment left available, and desperation (Karlawish et al., 2008; Sugarman, Cain, Wallace, & Welsh-Bohmer, 2001). In concordance with this view, we found that some participants viewed research as a “last resort” to treatment and were desperate to try anything that worked.

The context of research recruitment in acute illness care settings, in particular may have contributed more to uncertainty or misperceptions regarding the role of research. Morain, Joffe & Largent (2019) discuss the ethics of therapeutic misconception in the context of dual-role consent, or physician-investigators obtaining consent from patients whom they have had preexisting treatment relationships (Morain, Joffe, & Largent, 2019). Morain and colleagues argue that due to the common occurrence of therapeutic misconception is not a decisive argument against dual-role consent (Morain et al., 2019).

Comprehensive informed consent can help minimize therapeutic misconception and the false beliefs it can generate (McCormick, 2018). McCormick defines good informed consent as not a single event, but a continuous discussion where a participant is reminded of the voluntary nature of the research and that benefits to the participant are not expected (McCormick, 2018). In addition, there is currently no standardized measure of assessment for therapeutic misconception (Dunn & Palmer, 2017). Such a tool would be helpful in further defining the concept of therapeutic misconception and its implications for researchers, clinical staff, and participants.

It is important to distinguish therapeutic misconception from altruism. Altruism is defined as the desire to help research or to help others or the desire for future societal benefits (Dunn & Palmer, 2017; Sugarman et al., 2001). Unlike therapeutic misconception, being motivated to participate in research due to desire to help others is not cause for concern and is generally understood to be consistent with the goals and definition of research. In fact, altruistic motivations have been found to be an important motivational factor for decisions to participate in dementia research, particularly in studies that are not evaluating potential disease-modifying therapeutics (Avent et al., 2013; Carrera et al., 2018; Karlawish et al., 2009; Ries, Mansfield, & Sanson-Fisher, 2019; Sugarman et al., 2001). While the general purpose of research is broadly understood to be to produce generalizable knowledge, additional attention should be paid to the ethical implications of garnering participation in studies from which participants’ will not be able to realize any benefits. Findings from the present study highlight the potential that despite clear information presented in multiple modalities, motivations to participate may be driven by misattributed optimism for potential personal or familial benefit, favorable view of relationship with researcher, and altruistic motivations.

The present findings also highlight the importance of further evaluation of the operational frameworks that guide implementation of the principles of autonomy, beneficence, and justice. In this case, people living with dementia face challenges realizing justice in research due to the myriad barriers to their inclusion and when included – may be motivated to participate due to optimism regarding the potential personal benefits for research (Sugarman et al., 2001). The principle of autonomy indicates that decisions to contribute to new knowledge discoveries absent potential benefits, and assuming effective communication of relevant risks, should be recognized and accommodated although underlying assumptions that participants interpret risks and benefits in a manner equivalent with researchers may not inaccurate. Yet, the current paradigm for viewing benefits from IRBs focuses on a narrow conceptualization of benefits that is not responsive to the multidimensional considerations expressed by persons with dementia and caregivers in this study and others, encompassing perceived individual, familial, and societal benefits (Largent et al., 2014; Wertheimer 2014). A more unidimensional view of risks and benefits may consequentially disincentive adoption of more reciprocal or equitable models of participation that can extend into partnerships, where informed participants who are unable to benefit from the delayed realization of study results, might benefit through receipt of services or referrals to services to help address their immediate health needs (Gilmore-Bykovskyi et al., 2020). Such modest compensation for participation through the provision of services, education, and compensation for time may be too frequently presumed to constitute coercion for participants (Largent et al., 2014; Wertheimer 2014). Rather, such practices may indeed extend help address participation barriers or reduce misinterpretation of study benefits, by clarifying actual tangible benefits of participation rather than relying on ambiguous statements that participants are “unlikely to receive any direct benefit” as are commonly used. There is a need for further research in this area, and more robust considerations of the nuances surrounding the clarity of perceived multidimensional benefits of dementia research participation.

A common strategy to maximize alignment of planned research activities, including any potential benefits as well as procedural flexibilities (e.g. with scheduling) with participants’ values and preferences, is through stakeholder engagement and participatory frameworks. Employing these approaches involves active engagement of relevant stakeholders, including people living with dementia, throughout the research process. Such strategies recognize the unique contributions of “experts by experience” and allow for the modifications to study procedures that are informed by and result from the process of partnership. (Øksnebjerg et al., 2018; Stevenson & Taylor, 2019; Swarbrick et al., 2019). While inclusion of persons with ADRD in the research design process remains limited, broader uptake and successes of this approach are increasingly evident through recent research, demonstrating both the feasibility and utility of broader inclusion of persons with ADRD throughout the research process (Frank et al., 2020a; Frank et al., 2020b; Øksnebjerg et al., 2018; Stevenson & Taylor, 2019; Swarbrick et al., 2019).

The National Institute of Health Inclusion Across the Lifespan policy requires that individuals of all ages must be included in all human subjects research conducted or supported by the NIH, unless there are scientific or ethical reasons not to include them. Many individuals who are diagnosed continue to have decisional capacity in mild and sometimes moderate disease stages (Black et al., 2013; Slaughter, Cole, Jennings, & Reimer, 2007). Most institutional policies and practices that tie decision-making to a legally authorized representative are not required to first consider or elicit the person with ADRD’s perspective, although it is generally assumed this person acts in a way concordant with the person with ADRD, which has implications for flexibility and sequencing of specific procedures in recruitment protocols. A better understanding of health care provider beliefs about research participation of persons with ADRD is needed to inform strategies to overcome potential biases.

Limitations

Although saturation was achieved across themes, the number of participants in this study was small, especially among persons with ADRD, as such findings are likely not broadly generalizable to other regions and contexts. Given the limited number of people with ADRD recruited into our study, we were not able to effectively compare the views people with ADRD had towards participation in research to the views of caregivers and determine whether those views were converging or diverging. The present study did not directly partner with people living with ADRD in the conceptualization and design of the study. It is possible that more direct engagement with people living with ADRD could have yielded approaches that may have helped to overcome barriers to referrals surrounding acute illness care, or informed different approaches that probing perspectives regarding research participation. Additionally, most participants had a college degree, identified as white, and were English-speaking, the lack of more racial/ethnic and education-based diversity may have biased results toward more ethnocentric perspectives. Further research with more diverse populations is critical to understanding culturally-specific variations in views toward research participation, and associated ethical implications.

Conclusions

This article demonstrates several ethical and methodological complexities associated with research recruitment of people with ADRD and their caregivers in an acute illness care setting. Analyses presented herein suggest that the perceptions participants hold toward ADRD research and research recruitment efforts may contribute to misconceptions regarding the purposes and intent of ADRD research, which have implications for self or proxy decision-making and other relevant ethical consequences. Findings highlight the importance of multimodal approaches to ensure clarity across the hypothetical nature of study participation, and identify methodological considerations for achieving this.

Best Practices

Progress in understanding the views and preferences of ADRD research volunteers is undermined by a lack of approaches to documenting and addressing challenges to obtaining data from persons with ADRD and their caregivers. Careful documentation and discussion of problems encountered in efforts to elucidate participant perspectives toward ADRD research is imperative to timely identification of ethical and methodological challenges. In our study, participants had difficulty with answering hypothetical questions about participating in ADRD research; a finding that has been studied in other work (FeldmanHall et al., 2012; Fitzsimons & Shiv, 2001; Johnsson et al., 2010; Pardo, Midden, & Miller, 2002). Multimodal approaches to the recruitment and interview procedures, including the use of visuals such as a video, are a useful avenue to aid participants in better understanding the questions and reducing ambiguity regarding the abstract nature of participation. Engagement of a CAB to offer suggestions on interview materials can be helpful in ensuring common language, engaging format, and respect for participants from diverse backgrounds.

Research Agenda

Obtaining views and preferences people with ADRD and their caregivers have towards ADRD research and recruitment is foundational to efforts to enhance establish an applied, empiric science for informing research recruitment and engagement. Future research should consider empiric investigations to identify and compare experiential and scenario-based investigation of participant perspectives, and should extend these methods to investigations aimed at determining the success of these approaches in fostering more positive attitudes toward research. Our findings are limited in that only three people with ADRD were interviewed. A major priority for future research in this area is greater inclusion of persons with ADRD to develop an understanding of their unique research and recruitment preferences, and ways in which their perspectives to may vary from those of other stakeholders in ADRD research.

Educational Implications

Researchers should be mindful of potential ethical and methodological considerations when recruiting persons with ADRD and their caregivers through an acute illness care setting and in applied recruitment science investigations. In addition, researchers and ethics committee members should consider ways in which recruitment procedures can be adapted to facilitate more flexibility for diverse decisional preferences without violating ethical requirements regarding informed consent.