Retention of Study Partners in Longitudinal Studies of Alzheimer Disease

Abstract

Background:

Study partners are required for all participants at Alzheimer’s Disease Research Centers (ADRCs). Study partners’ attitudes and beliefs may contribute to missed visits and negatively impact retention of participants in longitudinal AD studies.

Objective:

Study partners (N = 212) of participants (Clinical Dementia Rating^® [CDR]≤2) at four ADRCs were randomly surveyed to examine their facilitators and barriers to continued participation in AD studies.

Methods:

Reasons for participation were analyzed with factor analysis and regression analysis. Effects of complaints and goal fulfillment on attendance were estimated with fractional logistic models. Open-ended responses were characterized with a Latent Dirichlet Allocation topic model.

Results:

Study partners participated for personal benefit and altruism. They emphasized personal benefits more when their participants had a CDR > 0 than when they had a CDR = 0. This difference declined with participant age. The majority of study partners rated their ADRC participation as positive and meeting their goals. Although half reported at least one complaint, very few regretted participating. Those who reported that ADRC participation fulfilled their goals or had fewer complaints were more likely to have perfect attendance. Study partners requested more feedback about test results and better management of study visits.

Conclusion:

Study partners are motivated by both personal and altruistic goals. The salience of each goal depends on their trust in researchers and the participant’s cognitive status and age. Retention may improve with perceived goal fulfillment and fewer complaints. Potential areas for improving retention are providing more information about the participant’s test results and better management of study visits.

Keywords

Adult children Alzheimer’s disease barriers facilitators spouse

INTRODUCTION

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects cognition and daily function. Given this, and that patients frequently lack insight into their impairment, all participants in AD clinical trials are required to enroll with a study partner. Study partners are family members or close friends who can provide valuable information about the cognitive, functional, and behavioral status of the participant over time [1–6]. They are often involved in a participant’s decision to enroll in AD trials and to attend study visits [6–11]. Study partners accompany participants to study visits, ensure compliance with study protocols, and report adverse effects experienced by the participant [3, 6, 8, 10]. Retention, or consistent completion of study visits by participants and study partners, is critical to the success of longitudinal AD studies. However, research about study partners’ facilitators and barriers to continued participation and their impact on retention in longitudinal AD studies is limited [7].

Similar to participants in longitudinal AD studies, study partners participate in hopes of medical benefit, access to experts and new treatments, altruism, and to contribute to AD research [7, 9, 12, 13]. In addition, barriers to study partners’ participation, more generally, include informed consent, comorbidities, medications, risk/fear of side effects, barriers with procedures, and medical burden for the participant, as well as travel and length and/or frequency of study visits [2, 7, 14]. Study partners’ facilitators and barriers to participation may vary by study partner type. Most study partners are spouses [9, 15, 16]. Compared to spouses, adult children may perceive greater health risks, such as side effects, from study procedures (e.g., annual assessments of clinical and neuropsychological function, magnetic resonance imaging, positron emission tomography imaging, lumbar punctures) and worse quality of life for their participant [15, 16]. Adult children may be less available to attend study visits than spouses, especially if they are employed or raising children [3, 9]. Spouses are more willing to participate in AD clinical trials [1, 15]. Limited evidence suggests that having a non-spouse study partner [3, 15, 17] or an unreliable study partner increases a participant’s risk of dropping out [18]. Research regarding study partner age and subsequent risk of dropout is mixed [3, 15].

Therefore, we administered a survey to 212 study partners and 443 participants at four Alzheimer Disease Research Centers (ADRCs) to identify perceived facilitators and barriers to ongoing research participation. Evidence of participants’ motivations for participation, concerns, goals, and desired enhancements and their impact on retention were published previously [13]. Additional research is needed to examine study partners’ attitudes and beliefs, because they may contribute to missed visits or changing study partners, or even impact retention of participants in AD observational or longitudinal studies or clinical trials. The purpose of this study was to examine study partners’ facilitators and barriers in longitudinal AD studies. Collectively, insights into participants’ and study partners’ participation could influence the development and success of retention strategies to support study partners and participants in longitudinal AD studies.

MATERIALS AND METHODS

Participants

Study partners and participants in this mixed methods study were recruited from four ADRCs funded by the National Institute on Aging (NIA): Knight ADRC at Washington University in St. Louis, University of Pittsburgh ADRC, University of Wisconsin ADRC, and University of California, Irvine ADRC. Study partners and participants were eligible if the participant: 1) was 45 years of age or older, 2) was currently enrolled in longitudinal studies, and 3) had a global Clinical Dementia Rating^® (CDR) [19] score of≤2 at their most recent clinical assessment. Study partners were not eligible if their participant was institutionalized and/or did not live in the geographic region of the ADRC.

Eligible study partners and separate participants were randomly selected and invited to participate in person or by phone between their annual ADRC visits. Prior to all study procedures, study partners and participants provided written informed consent or verbal consent. These procedures were approved by the Institutional Review Boards at all four ADRCs.

Study procedures

Study partners and participants completed a 20-min survey about facilitators and barriers to retention in longitudinal studies in-person using an iPad during a break at their annual ADRC visit, or via telephone with a trained rater. All data were collected using Research Electronic Data Capture (REDCap) [20]. Study partners and participants received a $5 gift card for participating. The National Alzheimer’s Coordinating Center Uniform Data Set was used to analyze demographic information for these study partners [21, 22].

Measures

We created a 57-item assessment, including the participant and study partner versions of the Perceived Research Burden Assessment [23] and two open-ended questions to assess study partners’ and participants’ perceived facilitators and barriers to continued participation in longitudinal AD studies. Items from the survey were ranked using a Likert scale from 1 (strongly disagree) to 5 (strongly agree), unless otherwise noted. The final survey is included in the Supplementary Material. Additional information about the development of the assessment is published elsewhere [13].

We also examined how study partners’ perceived fulfillment of their goals and their complaints about study participation affected their attendance rates. Attendance rates were the number of visits that the study partner attended divided by the total number of expected visits at the ADRC.

Statistical analyses

Data were entered directly into REDCap [20], a secure, web-based application with real-time validation. We used quality control programs to verify identification, evaluate consistency, and monitor recruitment and retention throughout the study. We computed response frequencies for all items and transcribed and thematically coded open-ended responses. Data analyses were conducted in STATA 15.1 (StataCorp, LLC, College Station, TX).

We performed principal component factor analysis to estimate and explain the latent structure of reasons for participation. We also used regression scoring to generate factor scores rotated with varimax (orthogonal) and promax (oblique) techniques. Regression analysis of the factor scores was by ordinary least squares with robust (Huber/White/sandwich) standard errors. The ordinary least squares models included interaction terms between cognitive impairment of the participant (CDR > 0) and the age of the participant. Attendance rates were analyzed with the procedure “fracreg” (fractional logistic regression). The analysis included controls for the ADRC site of the study partner. The topic models were estimated with “ldagibbs,” a Latent Dirichlet Allocation machine learning topic model.

RESULTS

Across the four ADRCs, 212 study partners completed the survey. Demographic characteristics for study partners by study partner type and overall are included in Table 1. The relationships of study partners to participants were 64% spouses, 18% adult children, 10% siblings or other relatives, and 8% other (non-familial) relationship, such as a friend or neighbor. The average age (years) of each type of study partners’ participants were: spouses (71.4; range 49– 98), adult children (78.2; range 57– 98), and other relatives (73.2; range 55– 100). Results from the 443 participants were published previously [13].

Table 1

Demographic characteristics of study partners by study partner type and overall

Study Partner Type
	Spouse		Adult Children		Other		Total
	(n = 135)		(n = 38)		(n = 39)		(n = 212)
Age, Mean (SD)	71.0	(8.7)	50.8	(8.5)	68.6	(11.2)	66.9	(11.9)
Gender, n (%)
Female	75	(56%)	30	(79%)	33	(85%)	138	(65%)
Male	60	(44%)	8	(21%)	6	(15%)	74	(35%)
Race/Ethnicity, n (%)
Black	10	(7%)	5	(13%)	5	(13%)	20	(9%)
Asian	10	(7%)	1	(3%)	2	(5%)	13	(6%)
White	113	(84%)	30	(79%)	30	(77%)	173	(82%)
Other	1	(1%)	1	(3%)	0	(0%)	2	(1%)
More than one race	1	(1%)	0	(0%)	1	(3%)	2	(1%)
Missing	0	(0%)	1	(3%)	1	(3%)	2	(1%)
Hispanic, n (%)
Yes	3	(2%)	1	(3%)	0	(0%)	4	(2%)
No	132	(98%)	37	(97%)	39	(100%)	208	(98%)
Years of Education, Mean (SD)	16.2	(2.9)	18.7	(13.8)	15.4	(2.6)	16.5	(6.4)
Missing, n (%)	2	(1%)	1	(3%)	2	(5%)	5	(2%)
Age of participant, Mean (SD)	71.4	(9.0)	78.2	(8.5)	73.2	(10.4)	72.9	(9.5)
Clinical Dementia Rating (CDR) of participant, n (%)
CDR = 0	85	(63%)	20	(53%)	26	(67%)	131	(62%)
CDR = 0.5	39	(29%)	11	(29%)	10	(25%)	60	(28%)
CDR = 1	10	(7%)	7	(18%)	3	(8%)	20	(9%)
CDR = 2	1	(1%)	0	(0%)	0	(0%)	1	(1%)

*Percentages have been rounded and may not total to exactly 100%.

Goals of participation and perceived satisfaction

Study partners’ general assessment of their participation was highly positive. Nearly all (>95%) agreed or strongly agreed that their participation was valuable and that they were accomplishing their goals for participation. A small share of study partners (<6%) agreed or strongly agreed that they regretted their decision to participate or that they had second thoughts about participation.

Perceived facilitators

Most study partners strongly agreed that their reason for supporting their partner’s participation was to advance AD research (85%) and to benefit society and future generations (80%; Fig. 1). The principal factor analysis of the reasons for supporting their partner’s participation identified two orthogonal dimensions: reasons involving personal benefits for the participant and reasons involving altruism (Table 2). The eigenvalues for the first three factors (2.71, 1.47, and 0.52) strongly supported a two-factor model. An oblique rotation revealed a weak (0.22) positive correlation between the dimensions, supporting an orthogonal model.

Fig. 1

Reasons for participation in ADRC.

Table 2

Factor^† and regression analyses of reasons for participation

AD, Alzheimer disease; OLS, ordinary least squares; CDR, Clinical Dementia Rating. ^†Varimax (orthogonal) rotation. The baseline survey respondent was a White female spouse of a participant with CDR = 0. All models included controls for ADRC site. **p < 0.01; *p < 0.05.

Study partners’ emphasis on personal benefit depended on the participants’ cognitive status and age. While study partners of participants who had a CDR > 0 generally emphasized personal benefits more than study partners of participants who had a CDR = 0, this difference varied with age. For participants who had a CDR = 0, study partners emphasized personal benefit more when the participant was older. For study partners of participants who had a CDR > 0, we found no relationship between participant age and emphasis on personal benefit. Thus, the difference in study partners’ emphasis on participating for personal benefit between CDR > 0 and CDR = 0 was largest for younger participants and attenuated as age increased. Turning to altruistic goals, study partners’ emphasis increased with their level of trust in medical researchers and had no statistically significant relationship with the participant’s CDR score or age.

Perceived barriers

Overall, about half of study partners (51%) endorsed at least one of the 19 possible types of complaints offered on the survey. Complaints with which at least 5% of study partners agreed or strongly agreed were: fatigue (15.2%), inconvenient travel (13.0%), distance (12.3%), physical pain (11.9%), breach of privacy (9.4%), visits too long (9.0%), emotional distress (8.1%), and difficulty keeping track of procedures (6.3%). Frequencies and types of complaints were generally consistent across age cohorts, sex, and race.

Effects of perceived fulfillment of one’s own goals and complaints on retention

For 208 of the 212 study partners surveyed, information was available about the number of possible (scheduled) study visits and the number of completed study visits as of January 25, 2021. The number of expected visits ranged from 0– 23. Overall, the attendance rate was high. For participants with at least two possible study visits (N = 184), 72% had perfect attendance, and the average attendance rate was 93% (SD = 16%).

Table 3 reports fractional logistic regression results estimating the effects of study partners’ perceived fulfillment of their goals and perceived complaints on their attendance rates. The analysis of attendance rates included only study partners with two or more possible visits and included a control variable for the total number of possible visits. The control variable ensured that the number of possible visits would not confound the analysis because, for example, the study partners most committed to the study may have both relatively high attendance rates and relatively long histories of visits.

Table 3

Perceived fulfillment of one’s own goals, complaints/barriers, and participation

	Attendance rate
Independent variables	Model 1	Model 2	Model 3
Accomplishing goals (range: 1– 5)	0.371* (0.185)	—	—
Number of complaints (range: 0– 19)	—	– 0.167* (0.080)	—
Fatigue	—	—	0.290 (0.183)
Inconvenient travel	—	—	– 0.173 (0.329)
Distance	—	—	0.459 (0.333)
Physical pain	—	—	0.006 (0.209)
Breach of privacy	—	—	– 0.212 (0.238)
Visits too long	—	—	– 0.046 (0.272)
Emotional distress	—	—	– 0.059 (0.210)
Difficulty keeping track of procedures	—	—	0.133 (0.215)
Sibling	– 0.590 (0.406)	– 0.623 (0.450)	– 0.569 (0.519)
Child	1.219* (0.597)	1.279* (0.546)	1.647* (0.835)
Other relationship	0.203 (0.626)	0.116 (0.664)	0.075 (0.625)
Black	– 0.548* (0.480)	– 0.686 (0.540)	– 0.986 (0.538)
Asian	– 2.227 (1.160)	– 2.188* (1.089)	– 2.243 (1.211)
Other race	– 0.234* (0.903)	– 0.146 (0.959)	– 0.560 (0.914)
Age of study partner	0.055* (0.023)	0.061** (0.022)	0.072* (0.032)
Total possible study visits	– 0.100** (0.032)	– 0.102** (0.031)	– 0.094* (0.037)
N	178	183	175

This table presents fractional logistic regression results for attendance rate, excluding participants with fewer than two possible visits. Log odds ratios are reported with standard errors in parentheses. All models include controls for ADRC site. **p < 0.01; *p < 0.05.

Study partners who reported that ADRC study participation fulfilled their goals for their participant had, on average, higher odds of having perfect attendance (OR = 1.45, 95% CI: 1.01– 2.08). Study partners with a higher number of complaints had lower odds of perfect attendance (OR = 0.85, 95% CI: 0.72– 0.99). None of the most common complaints (Fig. 2), on their own, achieved a statistically significant association with rate of attendance.

Fig. 2

Topic model of study partners’ suggestions to enhance their study experience.

Older study partners had, on average, higher attendance rates than younger study partners. Study partners who were adult children had higher attendance rates than those who were spouses (the baseline category in the statistical models). Indeed, adult children study partners had greater than three times the odds of perfect attendance than spouses (OR = 3.38, 95% CI: 1.05– 10.91 in Model 1, Table 3). We found no consistent statistically significant effect of gender or self-reported race on attendance.

Open-ended comments about improving participant study experience

The survey included an open-ended question, “What is the most important thing that ADRC researchers could do to enhance your and your [study partner relationship] experience with the study?” One hundred ninety-three study partners responded with a comment. These were typically brief, but some study partners offered several sentences. Figure 2 presents the results of a topic model summarizing these comments. The model excluded words with fewer than five letters and assumed comments focused on a small number of topics. We selected six topics based on model fit and the interpretability/coherence of the topics.

Many comments were positive and offered no criticism or suggestions. The largest topic, “satisfied with study,” captured these and accounted for 31% of all comments. Study partners’ suggestions and concerns fell into five categories. The largest of these topics (20%) included requests to provide more feedback about participants’ test results and performance at study visits. Study partners also raised concerns about the management of their study visits (14%) and study participation generally (13%). Study partners sought more information about AD and related research findings (11%) and about their participant’s progression to AD (10%).

For the small number of study partners (n = 10) who regretted participation or had second thoughts about their participation, their suggestions to enhance ADRC participation included: finding a cure for AD, providing information to improve the participant’s quality of life, ensuring that the study partner’s/participant’s health is a priority, sharing comprehensive AD results over time, shortening the length of visits and surveys, excluding the study partner, and being more tolerant of participants as they age.

DISCUSSION

We examined study partners’ facilitators and barriers to participation at four NIA-funded ADRCs [13]. Study partners influence participants’ enrollment in and attendance of study visits [6–11]. Strategies are needed to retain both participants and study partners and reduce missed visits. Our results with study partners are consistent with our previous research with participants [13] in multiple ways: 1) the structure of reasons for participation for study partners and participants, including personal benefit and altruism, which are related to trust in medical researchers and the participant’s CDR score; 2) the relationship between perceived fulfillment of one’s own goals and higher attendance; and 3) the primary topics of open-ended responses about enhancing the study experience.

These similarities indicate that a common set of retention strategies may be valuable for retaining study partners and participants. For example, personal benefits weigh more heavily for participants who have a CDR > 0 and their study partners than for participants without cognitive impairment (CDR = 0) and their study partners. Thus, for these participants and their study partners, retention strategies targeted at enhancing perceived personal benefits, such as providing more feedback on tests, could increase retention of participants and study partners. Further, this indicates that retention strategies should be flexible and adapt with any cognitive decline of the participant.

Regarding reasons for participation, personal benefit was emphasized by different study partners based on their participant’s age and cognitive status. Study partners of participants without cognitive impairment (CDR = 0) put more emphasis on personal benefit as their participant aged. However, there was no relationship between age and emphasis on personal benefit when the participant had a CDR > 0. Study partners of older participants without cognitive impairment (CDR = 0) may start to notice more cognitive changes due to aging and want to learn more about AD and have access to future treatments and medical center staff. Similar retention strategies for study partners of the oldest participants with (CDR = 0) and with cognitive impairment (CDR > 0) may be beneficial, because their study partners put similar emphasis on personal benefit compared to young participants. This calls for a more nuanced approach that considers attributes of participants and study partners to increase retention.

Retention strategies could also target altruistic motivations for participation, particularly among study partners with greater trust in medical researchers. Perceived facilitators to study partner participation included advancing AD research and benefits to society and future generations. Similar to previous research, the number of perceived barriers to participation endorsed by study partners was limited and included fatigue, inconvenient travel, distance, physical pain, breach of privacy, long visits, emotional distress, and difficulty keeping track of procedures [2, 14].

Our results indicate that study partners whose goals were met by participation or who had fewer complaints about participation were more likely to attend ADRC visits than those whose goals or complaints were not met/addressed. This has direct implications for missed visits in longitudinal AD studies. We found that adult children had higher attendance rates than spouses, which runs counter to the limited evidence that having a non-spouse study partner increases a participant’s risk of dropping out [3, 15, 17, 18]. While adult children made up a small proportion of study partners in this study, it is possible that these adult children may attend more visits because there is no one else to take the participant to the study visits, or that the participant’s performance could have direct implications for their own health and their children’s health. Unfortunately, we do not know why participants select non-spouse study partners. As such, it is imperative to identify study partners’ goals in conjunction with barriers to participation over time and utilize different strategies for adult children and spouses to positively impact retention [15]. For example, for spouses and siblings of participants with cognitive impairment (CDR > 0), strategies that emphasize addressing concerns about memory and access to expertise, resources, and future treatments may positively impact attendance. Study partners with higher trust in researchers may respond better to strategies that appeal to their altruistic goals for participation, such as to advance AD research and to benefit society, and efforts to share these advances with them.

Study partners’ open-ended responses provided additional opportunities to indicate factors in their participation in longitudinal AD study procedures. Although the majority of comments were positive, study partners’ complaints included management of their study visits, such as not explaining information fully or not ensuring participants’ understanding, pressuring participants, or using the same scenarios/questions every year, and study participation generally. Strategies to address these concerns may vary based on type of study partner. For example, adult children, who may be employed and raising their own families, may benefit from additional communication regarding study visits and procedures so they can plan accordingly [3, 9]. Additional suggestions from study partners included more feedback about participants’ test results/performance [24] and progression to AD as well as more information about AD and research findings, which align with participants’ suggestions [13]. ADRCs should consider providing updates about the participant’s functional changes over time, including more education about early signs of AD, or sharing more updates about research findings with participants and study partners via existing newsletters or events.

Although the results are informative, this study has limitations. Similar to our previously published findings with participants [13], study partners who participated in this study may have been more committed than study partners who dropped out. We do not know whether the facilitators and barriers identified for the enrolled study partners differed from those of individuals who stopped attending, because Institutional Review Boards have restrictions about contacting individuals who drop out. In addition, while adult children attended more visits than spouses, they made up a small proportion of study partners in this study. The ADRCs engaged in this study collect limited information about the characteristics of study partners. Thus, we do not know whether the adult children in this study were employed, had children of their own, or lived with the participant, which would have helped us to better understand our results and their impact on participation overall. The majority of study partners were White and non-Hispanic, which also affects the generalizability of our findings. Future research is needed to compare facilitators and barriers for study partners from more diverse groups. While the majority of the study partners’ participants had a CDR of 0 or 0.5, additional research is needed to examine facilitators and barriers for study partners of participants who have a CDR of 2 or 3 or study partners of participants with early-onset AD. Last, this study only included study partners at four ADRCs, which may not be generalizable to other ADRCs or to other, non-observational types of AD research.

Regardless, it is essential to examine study partners’ and participants’ facilitators and barriers to participation over time at ADRCs, especially if the participant’s cognitive status changes. These findings could be used to develop comprehensive strategies to meet the needs of adult children and spouse study partners as they age and manage their own health and families and their participants. ADRC sites should consider providing study partners with test results [24] or AD research updates to enable them to plan for the future. This could also increase their feelings of fulfillment, particularly for their goals involving personal benefit, and thereby positively impact retention for both study partners and participants in longitudinal AD studies.

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments to report.

FUNDING

This study was funded by the National Alzheimer’s Coordinating Center Collaborative Project, 2017-01, and supported by the National Institute on Aging, National Institutes of Health (NIA-NIH) R01AG054518 (PI: Lingler) and U01 AG015676 (PI: Stark). The National Institute on Aging, National Institutes of Health (NIA-NIH) Grant U01 AG016976 provided funding for the NACC database, which includes data from the NIA-funded ADRCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P50 AG047266 (PI Todd Golde, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Thomas Wisniewski, MD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG005131 (PI James Brewer, MD, PhD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG053760 (PI Henry Paulson, MD, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P30 AG049638 (PI Suzanne Craft, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), P50 AG005681 (PI John Morris, MD), P50 AG047270 (PI Stephen Strittmatter, MD, PhD).

The funders had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

CONFLICT OF INTEREST

Matthew Gabel is an Associate Editor of this journal but was not involved in the peer-review process nor has access to any information regarding its peer-review.

DATA AVAILABILITY

The data supporting the findings of this study are available on request from the corresponding author.

The supplementary material is available in the electronic version of this article: .

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