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Mistrust of Pediatric Sickle Cell Disease Clinical Trials Research

      Introduction

      Sickle cell disease (SCD) research is hampered by disparities in participation due in part to mistrust of research among racial/ethnic minorities. Beyond the historic context of research misconduct, little is known about the associations of social ecologic factors with mistrust and of mistrust with SCD clinical trials enrollment. This study evaluated proximal (age, gender, disease severity, perceived stress, SES) and distal (religious beliefs, social support, instrumental support) factors related to mistrust of research among caregivers of children with SCD and adolescents and young adults (AYAs) with SCD.

      Methods

      Over an 18-month period (2009–2010), participants completed questionnaires of perceived barriers and benefits to clinical trials enrollment, perceived stress, and self-reported demographic and disease-related information. Analyses (January–June 2015) used multivariable linear regressions to evaluate predictors of mistrust.

      Results

      Data were analyzed for 154 caregivers (mean age, 38.75 years; SD=9.56 years; 90.30% female) and 88 AYAs (mean age, 24.76 years; SD=7.25 years; 46.40% female). Among caregivers (full model, R2=0.14, p≤0.001), greater mistrust was explained by higher perceived stress (β=0.04, p=0.052); religious beliefs (β=0.61, p≤0.001); and greater instrumental support (β=0.07, p=0.044). Among AYAs (full model, R2=0.18, p≤0.001), higher mistrust was explained by being male (β=–0.56, p≤0.001) and lower instrumental support (β=–0.11, p=0.016). Mistrust was significantly greater among caregivers that reported no prior involvement in medical research (p=0.003).

      Conclusions

      By understanding the complexity through which social ecologic factors contribute to mistrust, researchers may create targeted strategies to address mistrust and increase engagement in SCD research for caregivers and AYAs.

      Introduction

      Sickle cell disease (SCD) affects approximately 70,000–100,000 Americans and is one of the most common chronic conditions affecting primarily racial and ethnic minorities (e.g., African ancestry, Hispanic, Mediterranean, and Asian descent).

      National Heart, Lung, and Blood Institute. Evidence Based Management of SCD. www.nhlbi.nih.gov/sites/www.nhlbi.nih.gov/files/sickle-cell-disease-report.pdf. Published 2014. Accessed January 23, 2016.

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      Mistrust is often linked to historic misconduct with minorities in research, particularly exploitation of African Americans in medical research (i.e., Tuskegee Syphilis Study).
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      mistrust is still prevalent and minorities remain under-represented in clinical trials research.
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      Studies among pediatric patients with SCD and their caregivers have focused on barriers to clinical trials enrollment, including study design and practical considerations (i.e., time and demands).
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      • et al.
      Randomization is not associated with socio-economic and demographic factors in a multi-center clinical trial of children with sickle cell anemia.
      Limited literature highlights mistrust of research as a significant barrier to clinical trials enrollment among the SCD community.
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      • et al.
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      Parental attitudes toward research participation in pediatric sickle cell disease.
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      • et al.
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      • Lebensburger J.D.
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      • Scarinci I.C.
      Exploring barriers and facilitators to clinical trial enrollment in the context of sickle cell anemia and hydroxyurea.
      Most of these studies used qualitative data gathered through focus groups of pediatric patients and their caregivers and were limited by small sample sizes, evaluated attitudes toward enrollment in a specific clinical trial, or evaluated attitudes toward the amount of SCD research conducted as opposed to perceived benefits and barriers toward research.
      • Liem R.I.
      • Cole A.H.
      • Pelligra S.A.
      • Mason M.
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      Parental attitudes toward research participation in pediatric sickle cell disease.
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      • et al.
      Barriers to hematopoietic cell transplantation clinical trial participation of African American and black youth with sickle cell disease and their parents.
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      • Scarinci I.C.
      Exploring barriers and facilitators to clinical trial enrollment in the context of sickle cell anemia and hydroxyurea.
      Additionally, none evaluated factors related to mistrust of research. More effective redress of the barrier of mistrust requires increased understanding of disease-related and psychosocial contributors, which will allow researchers to frame SCD research in a manner that gains community acceptance and increases informed consent.
      Relevant to this effort, prior work systematically evaluated perceived benefits and barriers of pediatric clinical trials enrollment for SCD and asthma patients and their caregivers based on The Social Ecologic Model.
      • Barakat L.P.
      • Patterson C.A.
      • Mondestin V.
      • et al.
      Initial development of a questionnaire evaluating perceived benefits and barriers to pediatric clinical trials participation.
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      • Mondestin V.
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      • Barakat L.P.
      Clinical trial decision-making in pediatric sickle cell disease: a qualitative study of perceived benefits and barriers to participation.
      The social ecology of children with chronic health conditions describes multiple, bidirectional influences on a child and family’s adaptation to the chronic condition. These influences, from proximal to distal variables and organized at each level of a child’s social ecology, are patient, caregiver and family, community, and society/culture.
      • Kazak A.E.
      A contextual family/systems approach to pediatric psychology: introduction to the special issue.
      Factors affecting research participation may connect to factors influencing mistrust. For example, perceived severity of a child’s illness (a patient-level variable) has been noted as a factor affecting parents’ willingness to allow their child to participate in research.
      • Wynn L.
      • Miller S.
      • Faughnan L.
      • et al.
      Recruitment of infants with sickle cell anemia to a Phase III trial: data from the BABY HUG study.
      Disease severity can increase stress and anxiety among caregivers and patients, particularly in families that are challenged with management of SCD-related complications,
      • Gil K.M.
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      • Porter L.S.
      • et al.
      Daily stress and mood and their association with pain, health-care use, and school activity in adolescents with sickle cell disease.
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      The role of stress and mood in sickle cell disease pain: an analysis of daily diary data.
      and an association between perceived stress and greater mistrust among caregivers of children with SCD and asthma has been established.
      • Barakat L.P.
      • Patterson C.A.
      • Mondestin V.
      • et al.
      Initial development of a questionnaire evaluating perceived benefits and barriers to pediatric clinical trials participation.
      Additionally, minorities may experience stress related to economic difficulties (a family-level variable). Researchers have made attempts to reduce SES-related barriers to research participation by offering instrumental support, or tangible and physical support provided to assist people with participating in a clinical trial (e.g., compensation, transportation, child care, access to care).

      Support & Social Conflict: Section One—Social Support. Psychosocial Notebook 2008. www.macses.ucsf.edu/research/psychosocial/socsupp.php. Accessed December 15, 2015.

      Successful use of these supports to encourage participation in clinical trials has been mixed, with some suggesting incentives are an effective recruitment strategy and others noting that incentives have no impact on parents’ decisions to enroll their child in research.
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      Other factors that influence minority research participation, potentially contributing to mistrust of research, include religious beliefs countering medical science
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      and social supports (e.g., family and friends support research participation).
      • Barakat L.P.
      • Patterson C.A.
      • Mondestin V.
      • et al.
      Initial development of a questionnaire evaluating perceived benefits and barriers to pediatric clinical trials participation.
      Minority families have strong religious beliefs and supportive social networks that are often extremely important within their community. Although medical decision making and healthcare utilization are often influenced by religion and social networks (a society/culture variable),
      • Pullen E.
      • Perry B.
      • Oser C.
      African American women’s preventative care usage: the role of social support and racial experiences and attitudes.
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      • Ellison C.G.
      • Larson D.B.
      Explaining the relationships between religious involvement and health.
      it is unclear how and to what extent religion and social support influence mistrust.
      The purpose of this study was to evaluate proximal (age, gender, disease severity, perceived stress, and SES) and distal (religious beliefs, social support, and instrumental support) social ecologic factors as contributors to mistrust among caregivers of children with SCD and adolescents and young adults (AYAs) with SCD. It was hypothesized that greater disease severity, greater perceived stress, religious beliefs countering medical science, and lower social and instrumental support would be associated with greater mistrust of research and having an older child or being an older AYA, being male, and having lower SES would be associated with greater mistrust. Furthermore, greater mistrust was expected to be associated with no prior involvement in research.

      Methods

      This study was performed using data from a multisite study, which evaluated perceived benefits and barriers to pediatric clinical trials participation through development and initial validation of the Pediatric Research Participation Questionnaire (PRPQ).
      • Barakat L.P.
      • Patterson C.A.
      • Mondestin V.
      • et al.
      Initial development of a questionnaire evaluating perceived benefits and barriers to pediatric clinical trials participation.
      • Patterson C.A.
      • Chavez V.
      • Mondestin V.
      • Deatrick J.
      • Li Y.
      • Barakat L.P.
      Clinical trial decision-making in pediatric sickle cell disease: a qualitative study of perceived benefits and barriers to participation.
      The PRPQ was developed in four phases that included item generation from the project team, community partners, and SCD medical experts; tailoring of the items for caregivers and for AYAs and children with SCD or asthma; review of the measure by stakeholders; and pilot testing to ensure clarity and ease of administration. The study protocol was approved by the appropriate IRBs. Data were collected over an 18-month period in 2009–2010. An exploratory factor analysis was conducted to identify latent structures of the questionnaire of which mistrust of research/researchers was identified as a primary consideration affecting decisions to participate in clinical trials.
      • Barakat L.P.
      • Patterson C.A.
      • Mondestin V.
      • et al.
      Initial development of a questionnaire evaluating perceived benefits and barriers to pediatric clinical trials participation.

      Study Sample

      In the parent study, 296 of 385 (77.1%) consented to participate; 20.1% (n=78) refused participation; and 2.8% (n=11) did not meet inclusion criteria. Reasons for refusal are described elsewhere.
      • Barakat L.P.
      • Patterson C.A.
      • Mondestin V.
      • et al.
      Initial development of a questionnaire evaluating perceived benefits and barriers to pediatric clinical trials participation.
      For this secondary analysis, only caregivers of children with SCD (n=154) and AYAs (aged ≥16 years) with SCD (n=88) were included. Participants were recruited from East Coast pediatric SCD centers and an adult outpatient clinic associated with the medical universities that provided care for many AYA patients that transitioned out of pediatric care. All participants completed the PRPQ on paper and in private during clinic appointments. A research assistant was available to address health literacy issues. The PRPQ assessed attitudes (with a binary response category of agree or disagree) toward medical and psychosocial research studies to aid in understanding decision making about clinical trials enrollment.

      Measures

      Mistrust of research/researchers, social support, and instrumental support (tangible or physical support offered to encourage trial participation) were factors identified in the exploratory factor analysis of the PRPQ as contributors to clinical trials enrollment decisions. The items that loaded on these factors were used to compute a total score, with higher scores indicating greater levels of mistrust, social support, and instrumental support (Table 1). Reliability was adequate for each of these variables among caregivers and AYAs (mistrust, α=0.70 and α=0.66; social support, α=0.76 and α=0.80; instrumental support, α=0.70 and α=0.68; respectively).
      Table 1Study Measures
      Mistrust of research/researchers
      Total score of the following items:
      • 1)
        We participate in research because the healthcare team takes good care of my child
        Items did not load on the mistrust factor of the PRPQ but were added to mistrust measure because they were identified as barriers to research participation related to mistrust. The addition of these items resulted in greater reliability.
      • 2)
        The government sometimes exposes research participants to medicine and procedures known to be harmful to one’s health
        Items did not load on the mistrust factor of the PRPQ but were added to mistrust measure because they were identified as barriers to research participation related to mistrust. The addition of these items resulted in greater reliability.
      • 3)
        Research is a part of a conspiracy to harm minority groups
      • 4)
        We are willing to participate in research when we know exactly what we will be asked to do
        Items did not load on the mistrust factor of the PRPQ but were added to mistrust measure because they were identified as barriers to research participation related to mistrust. The addition of these items resulted in greater reliability.
      • 5)
        The healthcare team will view me/my child only as a research participant if I enroll
      • 6)
        The healthcare team will treat me/my child differently if I enroll
      • 7)
        When the researcher is of the same race I am more likely to participate
      • 8)
        Researchers sometimes hide information from participants prior to research
      • 9)
        Researchers ask for financial information that may get back to the government and cause me to lose my check/benefits
      • 10)
        Personal information given in research does not stay private and might hurt me/people I care about
      • 11)
        Researchers are motivated by their own career goals and not the welfare of their participants
      Social support of research participation
      Total score of the following items:
      • 1)
        My family would want me/my child to be in research
      • 2)
        My friends would want me/my child to be in research
      • 3)
        My religious leader would want me/my child to be in research
      • 4)
        My community agency would want me/my child to be in research
      Instrumental support for research
      Total score of the following items:
      • 1)
        I/We would participate in research if we could learn more about my/my child’s illness
      • 2)
        I/We would participate in research if we could get tests/medicine my insurance won’t cover
      • 3)
        I/We would participate in research if we could get tests or medicine not available to the public
      • 4)
        More people would participate in research if researchers provide childcare
      • 5)
        More people would participate in research if researchers provide money or gifts
      • 6)
        More people would participate in research if researchers cover transportation costs
      • 7)
        More people would participate in research if researchers provide telephone/internet participation
      Religious beliefs
      Endorsement of the following item:
      • 1)
        Researchers sometimes undermine the power of God and God’s will.
      • 2)
        My religious leader would want me/my child to be in research.
      Note: All items were derived from the Pediatric Research Participation Questionnaire (PRPQ) and loaded on one of the four-factor structures that were identified during an exploratory factor analysis of the PRPQ (Barakat et al., 2013).
      • Barakat L.P.
      • Patterson C.A.
      • Mondestin V.
      • et al.
      Initial development of a questionnaire evaluating perceived benefits and barriers to pediatric clinical trials participation.
      a Items did not load on the mistrust factor of the PRPQ but were added to mistrust measure because they were identified as barriers to research participation related to mistrust. The addition of these items resulted in greater reliability.
      Religious beliefs were assessed through one item of the PRPQ that reads: Researchers sometimes undermine the power of God and God’s will. In addition, one item of the social support scale asked participants if their religious leader would want me/my child to be in research (Table 1).
      The Perceived Stress Scale four-item short form of the 14-item measure evaluated the degree to which participants perceived their lives as stressful. The Perceived Stress Scale showed acceptable reliability in prior validation studies.
      • Cohen S.
      • Kamarck T.
      • Mermelstein R.
      A global measure of perceived stress.
      Reliability was adequate for caregivers (α=0.66) and marginal for AYAs (α=0.53).
      • Barakat L.P.
      • Patterson C.A.
      • Mondestin V.
      • et al.
      Initial development of a questionnaire evaluating perceived benefits and barriers to pediatric clinical trials participation.
      Participants completed a General Information Form to collect demographic and disease-related information and prior involvement in medical research (coded as yes/no). Disease severity was assessed by SCD genotype; healthcare utilization (total number of daily medications, treatments, and hospitalizations in the past year); and SCD complications (total number of medical and psychosocial diagnoses). Demographics included age of child/AYA with SCD, gender of caregiver or AYA completing the questionnaire, education level of caregiver or AYA, and monthly household income.

      Statistical Analysis

      Analyses were conducted separately for caregivers and AYAs during January–July 2015. Descriptive statistics were computed for all study variables checking for outliers and distribution. Fisher exact tests, t-tests, Spearman correlations, and linear regressions were used for hypothesis testing. All variables correlated with mistrust (p≤0.10) were included in the linear regression models. Hierarchical linear regression models were computed based on the Social Ecologic Model from proximal to more distal—patient- and family-level variables on the first step (demographics, disease severity, perceived stress, and SES) and community-level variables on the second step (instrumental support, beliefs about religion, and social support) (Figure 1). A two-sided p-value <0.05 was considered statistically significant for hypothesis testing. Power was >0.80 for detecting medium effects with 0.05 Type I error. All of the analyses were performed in SPSS, version 22.
      Figure thumbnail gr1
      Figure 1Factors related to mistrust of clinical trials research: social ecologic framework.

      Results

      Participants included 154 caregivers (mean age, 38.75 years; SD=9.56 years) and 88 AYAs (mean age, 24.76 years; SD=7.25 years) (Table 2). Majority of caregivers and AYAs self-identified as Black or African American (caregivers, 92.20%; AYAs, 96.60%) and all participants self-identified as Non-Hispanic/Latino. SCD genotype SS was most common among AYAs (73.90%) and the children of the caregivers (59.70%). Mistrust, instrumental support, and social support scores did not differ significantly between caregivers and AYAs.
      Table 2Participant Demographic, Medical, and Summary Score Characteristics
      DemographicsCaregiver, n (%) (n=154)Adolescent and young adult, n (%) (n=88)
      Gender
       Female139 (90.30%)41 (46.60%)
       Male15 (9.70%)47 (53.40%)
      Age (years), M (SD)38.75 (9.56)24.76 (7.25)
      Ethnicity
       Non-Hispanic/Latino154 (100.00%)88 (100.00%)
      Race
       Black or African American142 (92.20%)85 (96.60%)
       White3 (1.90%)2 (2.30%)
       Other9 (5.90%)1 (1.10%)
      Education
       Some high school11 (7.10%)27 (30.70%)
       High school graduate48 (31.20%)23 (26.10%)
       Some college/vocational school45 (29.20%)28 (31.80%)
       Bachelor’s degree34 (22.10%)9 (10.20%)
       Professional/graduate school16 (10.40%)1 (1.10%)
      Ever participated in research?
       Yes95 (61.70%)47 (53.40%)
       No59 (38.30%)41 (46.60%)
      SCD genotype
       SS92 (59.70%)65 (73.90%)
       SC42 (27.30%)19 (21.60%)
       SB+thal20 (13.00%)4 (4.50%)
      Healthcare utilization,
      Total number of daily medications, treatments, and hospitalizations in the past year.
      M (SD)
      4.67 (3.15)6.97 (8.13)
      Number of health complications,
      Total number of medical and psychosocial diagnoses.
      M (SD)
      0.22 (0.55)0.44 (0.93)
      Mistrust score,
      Mistrust scores were skewed and thus transformed using the square root transformation (caregiver M=1.09, SD=0.80; adolescent and young adult M=1.32, SD=0.78).
      ,
      There were no significant differences between caregivers and adolescent and young adults with sickle cell disease.[yank1]?>
      M (SD)
      1.83 (1.96)2.35 (2.04)
      Social support score,
      There were no significant differences between caregivers and adolescent and young adults with sickle cell disease.[yank1]?>
      M (SD)
      3.42 (1.05)3.31 (1.18)
      Instrumental support score,
      There were no significant differences between caregivers and adolescent and young adults with sickle cell disease.[yank1]?>
      M (SD)
      5.32 (1.74)5.19 (1.78)
      SCD, sickle cell disease.
      a Total number of daily medications, treatments, and hospitalizations in the past year.
      b Total number of medical and psychosocial diagnoses.
      c Mistrust scores were skewed and thus transformed using the square root transformation (caregiver M=1.09, SD=0.80; adolescent and young adult M=1.32, SD=0.78).
      d There were no significant differences between caregivers and adolescent and young adults with sickle cell disease.[yank1]?>
      Among caregivers, greater instrumental support (r =0.18, p=0.02) and religious beliefs countering medical science (r=0.28, p≤0.000) were significantly correlated with greater mistrust of research (Table 3). There was a trend toward significance for higher perceived stress with greater mistrust among caregivers (r=0.15, p=0.069). Among AYAs, lower instrumental support was significantly correlated with lower mistrust (r=–0.25, p=0.19). Mistrust differed significantly between female AYAs (mean=1.03, SD=0.79) and male AYAs (mean=1.58, SD=0.69, p≤0.001). Variables found to be associated with mistrust (p<0.10) for caregivers (perceived stress, religious beliefs, and instrumental support) and AYAs (gender and instrumental support) were further evaluated as predictors of mistrust in regression analyses.
      Table 3Correlates of Mistrust of Clinical Trials Research (Spearman’s Rho Correlations)
      VariablesCaregiver mistrust (n=154)Adolescent and young adult mistrust (n=88)
      Proximal variables-demographics
       Patient age–0.05–0.02
       Participant gender–0.05–0.34***
       Education level–0.09–0.06
       Monthly household income–0.120.04
      Proximal variables-disease-related
       SCD genotype–0.070.04
       Healthcare utilization–0.110.07
       Healthcare complications–0.11–0.09
      Distal variables
       Perceived stress0.15–0.03
       Instrumental support0.18*–0.25*
       Social support–0.06–0.14
       Religious beliefs0.28***0.14
      Note: Boldface indicates a trend relationship (p<0.10) or statistical significance (*p<0.05; **p<0.01; ***p<0.001).
      SCD, sickle cell disease.
      For caregivers, higher perceived stress contributed significantly to greater mistrust (β=0.05, p=0.028) (Table 4). Religious beliefs and instrumental support were added to the model and were also identified as significant predictors of mistrust (β=0.61, p=0.000 and β=0.07, p=0.044, respectively), such that religious beliefs countering medical science and greater instrumental support predicted greater mistrust among caregivers. Collectively, perceived stress, religious beliefs, and instrumental support explained 14% of the variation in mistrust (full model, F[3,148]=8.24, R2=0.14, p=0.000). Among AYAs, patient gender contributed significantly to mistrust, with male AYAs having greater mistrust as compared with female AYAs (β=–0.55, p=0.000). Instrumental support was also a significant independent predictor of greater mistrust (β=–0.11, p=0.016). Both gender and instrumental support explained 18% of the variance in mistrust (full model, F[2,85]=4.88, R2=0.18, p=0.000).
      Table 4Predictors of Mistrust of Clinical Trials Research (Hierarchical Regression Analyses)
      Variablesβp-value
      Caregivers (n=154)
       Model summary 1
      • R2=0.032
      • Adj. R2=0.025
      • Sig=0.028
      Perceived stress0.05 0.028*
       Model summary 2
      • R2=0.143
      • Adj. R2=0.126
      • Sig<0.001
      • Perceived stress
      • Religious beliefs
      • Instrumental support
      • 0.04
      • 0.61
      • 0.07
      •  0.052*
      • <0.001***
      •  0.044*
      Adolescents and young adults (n=88)
       Model summary 1
      • R2=0.126
      • Adj. R2=0.116
      • Sig=0.001
      Participant gender–0.55<0.001***
       Model summary 2
      • R2=0.184
      • Adj. R2=0.165
      • Sig<0.001
      • Patient gender
      • Instrumental support
      • –0.56
      • –0.11
      • <0.001***
      •  0.016*
      Note: Boldface indicates statistical significance (*p<0.05; **p<0.01; ***p<0.001).
      Adj., adjusted; Sig, significance.
      Mistrust was significantly greater in caregivers that reported no prior involvement in medical research (mean=1.33, SD=0.77) compared with caregivers that reported prior involvement (mean=0.94, SD=0.79, t[152]=3.02, p=0.003, d=0.51). There was no significant difference in mistrust based on prior involvement in medical research for AYAs.

      Discussion

      Mistrust has been cited as a barrier to clinical trials enrollment among the SCD community.
      • Haywood C. Jr
      • Lanzkron S.
      • Bediako S.
      • et al.
      Perceived discrimination, patient trust, and adherence to medical recommendations among persons with sickle cell disease.
      • Liem R.I.
      • Cole A.H.
      • Pelligra S.A.
      • Mason M.
      • Thompson A.A.
      Parental attitudes toward research participation in pediatric sickle cell disease.
      • Omondi N.A.
      • Ferguson S.E.
      • Majhail N.S.
      • et al.
      Barriers to hematopoietic cell transplantation clinical trial participation of African American and black youth with sickle cell disease and their parents.
      • Lebensburger J.D.
      • Sidonio R.F.
      • Debaun M.R.
      • Safford M.M.
      • Howard T.H.
      • Scarinci I.C.
      Exploring barriers and facilitators to clinical trial enrollment in the context of sickle cell anemia and hydroxyurea.
      This study is among the first to evaluate factors of mistrust beyond well-known historic mistreatment of African Americans in research in a sample of pediatric patients with SCD and their caregivers. SCD disproportionately affects racial/ethnic minorities

      National Heart, Lung, and Blood Institute. Evidence Based Management of SCD. www.nhlbi.nih.gov/sites/www.nhlbi.nih.gov/files/sickle-cell-disease-report.pdf. Published 2014. Accessed January 23, 2016.

      ; therefore, this was a unique opportunity to systematically evaluate mistrust to improve engagement in clinical trials. Findings indicate that perceived stress, religious beliefs, and instrumental support are predictors of mistrust among caregivers of children with SCD and that gender and instrumental support are predictors of mistrust among AYAs with SCD.
      Higher caregiver perceived stress, a proximal social ecologic factor, was found to significantly contribute to greater mistrust, consistent with prior work, revealing the same relationship for caregivers of children with SCD or asthma.
      • Barakat L.P.
      • Patterson C.A.
      • Mondestin V.
      • et al.
      Initial development of a questionnaire evaluating perceived benefits and barriers to pediatric clinical trials participation.
      Although not a primary finding of this study, associations were identified for education level with perceived stress, and monthly household income with perceived stress, suggesting that among this sample, stress was associated with lower SES. This association likely impacts mistrust and decisions regarding clinical trials enrollment, but in indirect ways. Demographic and disease severity variables accounted for low percentage of variance in mistrust, despite having sufficient power to detect small to medium effects; thus, the relationship of demographics or SCD severity with mistrust is likely complex. Further, the role of perceived stress in mistrust may not be exclusive to the SCD community, but rather an indication of mistrust across racial/ethnic minorities.
      Researchers have tried to address SES-related difficulties by offering instrumental support or incentives to decrease barriers and encourage enrollment; however, present findings reveal that greater instrumental support is associated with greater mistrust for caregivers. Caregivers may believe that researchers attempt to buy their participation by offering incentives or increase the amount of incentives to mask the risks of participation. In addition, the role of greater instrumental support in mistrust may also be the result of a psychological phenomenon known as “stereotype threat,”
      • Steele C.M.
      • Aronson J.
      Stereotype threat and the intellectual test performance of African Americans.
      aroused when a patient is aware of belonging to a negatively stereotyped group, evaluates cues where the stereotype is relevant, and ultimately becomes dissatisfied with healthcare-related interactions.
      • Aronson J.
      • Burgess D.
      • Phelan S.M.
      • Juarez L.
      Unhealthy interactions: the role of stereotype threat in health disparities.
      For SCD, instrumental support used to encourage enrollment may elicit greater mistrust, as these predominantly racial/ethnic minority communities may feel that acceptance of incentives confirms negative stereotypes. Future studies are needed to evaluate stereotype threat in the context of disparities in research participation.
      Religious beliefs countering medical science, a community-level social ecologic factor, was identified as a predictor of greater mistrust among caregivers of children with SCD. Although assessed with only two items, this finding is consistent with published studies
      • Kibler J.L.
      • Brisco K.
      Evaluation of a brief questionnaire for assessing barriers to research participation.
      • Daverio-Zanetti S.
      • Schultz K.
      • del Campo M.A.
      • Malcarne V.
      • Riley N.
      • Sadler G.R.
      Is religiosity related to attitudes toward clinical trials participation?.
      • Rivers D.
      • August E.M.
      • Sehovic I.
      • Lee Green B.
      • Quinn G.P.
      A systematic review of the factors influencing African Americans’ participation in cancer clinical trials.
      that have noted the significance of religion among racial/ethnic minorities, the belief that disease-related outcomes are under the control of God, and the relationship between religion and clinical trials participation. Researchers have taken into account the role of religiosity and have included religious institutions as effective venues for health-based programs and clinical trials enrollment.
      • Frew P.M.
      • Omer S.B.
      • Parker K.
      • et al.
      Delivering a “dose of hope”: a faith-based program to increase older African Americans’ participation in clinical trials.
      • DeHaven M.J.
      • Hunter I.B.
      • Wilder L.
      • Walton J.W.
      • Berry J.
      Health programs in faith-based organizations: are they effective?.
      However, it is important to consider religious institutions not only as means to encouraging clinical trials participation but also as trusted sources for disseminating general health information. Encouraging religious institutions and leaders to understand the importance of health promotion may increase the likelihood of researchers gaining community acceptance and breaking down mistrust.
      Factors that influence mistrust for AYAs with SCD vary from those of caregivers. The most proximal factor contributing to AYA mistrust was gender. Male AYAs with SCD were found to have significantly greater mistrust than female AYAs. Male African Americans are under-represented in biomedical research, and a lack of trust has been noted as the primary source.
      • Byrd G.S.
      • Edwards C.L.
      • Kelkar V.A.
      • et al.
      Recruiting intergenerational African American males for biomedical research studies: a major research challenge.
      • Diaz V.A.
      • Mainous A.G. 3rd
      • McCall A.A.
      • Geesey M.E.
      Factors affecting research participation in African American college students.
      When they do participate, they are motivated by civic duty, personal or family history of the disease, and compensation.
      • Byrd G.S.
      • Edwards C.L.
      • Kelkar V.A.
      • et al.
      Recruiting intergenerational African American males for biomedical research studies: a major research challenge.
      Compensation (e.g., money and gifts) was an incentive captured on the measure of instrumental support; however, unlike caregivers, use of fewer incentives in research contributed to greater mistrust among AYAs. This finding is not surprising; AYAs endorse the use of incentives during recruitment and retention strategies.
      • Jones F.C.
      • Broome M.E.
      Focus groups with African American adolescents: enhancing recruitment and retention in intervention studies.
      The AYAs in this study, having had a chronic health condition throughout their lifetimes, may feel that participating in SCD research is less of a risk and that incentives are a greater benefit. Additionally, they may not consider the use of incentives as a stereotype threat. Based on these findings, researchers should approach the use of incentives with caution and sensitivity, particularly in studies where parental permission for child participation is needed, given how instrumental support differs across AYAs and caregivers in terms of mistrust.

      Limitations

      These findings are subject to potential limitations. First, mistrust is one among a number of perceived barriers that may deter enrollment in clinical trials research. Others include study design and logistics (e.g., time and location of study site)
      • Wynn L.
      • Miller S.
      • Faughnan L.
      • et al.
      Recruitment of infants with sickle cell anemia to a Phase III trial: data from the BABY HUG study.
      • Barakat L.P.
      • Patterson C.A.
      • Mondestin V.
      • et al.
      Initial development of a questionnaire evaluating perceived benefits and barriers to pediatric clinical trials participation.
      • Patterson C.A.
      • Chavez V.
      • Mondestin V.
      • Deatrick J.
      • Li Y.
      • Barakat L.P.
      Clinical trial decision-making in pediatric sickle cell disease: a qualitative study of perceived benefits and barriers to participation.
      • Kennedy B.M.
      • Burnett M.F.
      Clinical research trials: factors that influence and hinder participation.
      ; however, the decision to further evaluate factors related to mistrust of research beyond historic mistreatment of racial/ethnic minorities was warranted based on preliminary findings and lack of current literature in this area. Second, this analysis was conducted with a mistrust measure with only initial support for its validity. There are several clinically validated scales that measure mistrust,
      • Kennedy B.M.
      • Burnett M.F.
      Clinical research trials: factors that influence and hinder participation.
      • Shelton R.C.
      • Winkel G.
      • Davis S.N.
      • et al.
      Validation of the group-based medical mistrust scale among urban black men.
      • Anderson L.A.
      • Dedrick R.F.
      Development of the Trust in Physician Scale: a measure to assess interpersonal trust in patient-physician relationships.
      • Rose A.
      • Peters N.
      • Shea J.A.
      • Armstrong K.
      Development and testing of the health care system distrust scale.
      • Zheng B.
      • Hall M.A.
      • Dugan E.
      • Kidd K.E.
      • Levine D.
      Development of a scale to measure patients’ trust in health insurers.
      • Hall M.A.
      • Camacho F.
      • Dugan E.
      • Balkrishnan R.
      Trust in the medical profession: conceptual and measurement issues.
      but most measure mistrust within the context of the healthcare system and not clinical trials, are not theoretically derived, or have not been validated in a sample of patients with chronic health conditions. Future studies may use one of these scales in addition to the PRPQ to measure mistrust as it relates to decisions about participating in clinical trials. Lastly, the participants were recruited primarily from comprehensive pediatric sickle cell centers where exposure to research is more prevalent. Thus, predictors of mistrust may be different in patients treated by providers in the community, patients who declined participating in the parent study, and patients with other chronic health conditions that may not expose them to frequent interactions within the healthcare system.

      Conclusions

      Despite these limitations, information from this study may allow researchers to address both proximal and distal factors related to mistrust through recruitment, informed consent, and retention strategies; however, historic contributions cannot and should not be diminished or viewed as a less important cause of mistrust. One such strategy that has been effective in prior work among children with SCD and families could include the use of a patient navigator to address the identified social ecologic factors associated with mistrust, among other barriers to participation, while educating on the potential benefits in order to improve the decision-making process.
      • Daniel L.C.
      • Li Y.
      • Smith K.
      • et al.
      Lessons learned from a randomized controlled trial of a family-based intervention to promote school functioning for school-age children with sickle cell disease.
      As the findings in this analysis have revealed, acknowledgement of religious beliefs and stressors related to SES, consideration for the appropriateness and types of incentives, and tailoring research and informed consent processes for specific subgroups may reduce the disparities in research participation and ultimately improve SCD treatments and outcomes.

      Acknowledgments

      Publication of this article was supported by the Centers for Disease Control and Prevention.
      This study was funded by a grant from the National Center for Minority Health and Health Disparities (1RC1MD004418).
      Chavis A. Patterson, PhD, was previously affiliated with St. Christopher’s Hospital for Children/Drexel University School of Medicine, Philadelphia, Pennsylvania. Lamia P. Barakat, PhD, was previously affiliated with Drexel University, Philadelphia, Pennsylvania.

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