Pediatric biorepository participation during the COVID-19 pandemic: predictors of enrollment and biospecimen donation

Throughout the COVID-19 pandemic, there has been a paucity of research among school-age children, even though many mitigation strategies disproportionately affect youth (e.g., closing schools but opening non-essential businesses in some settings) [1, 2]. Despite vaccination rolling out among those ≥12 years of age in the fall of 2021, cases among children and adolescents continue to rise, especially in unvaccinated children [3]. The impact of COVID-19 in pediatric populations likely depends on host susceptibility, symptoms, viral load, inoculum, social contact patterns, and behaviors. Studies assessing age-dependent susceptibility to and transmission of COVID-19 have multiple limitations [4]. Research with stored pediatric biospecimens has unique potential to inform key questions about immune responses to COVID-19 infection and inform further research about drivers of the pandemic. In contrast to adult biorepositories, pediatric biorepositories face distinct challenges to consent and thus representative inclusion in research; participants are minors and are considered a vulnerable population, and third-party approval is needed (i.e., from legal guardians) [5]. Enrolling participants that are representative of the pediatric population is essential for the validity, reliability, and interpretation of studies using collected samples. Most research efforts have focused on the effects of the SARS-CoV-2 virus on adult and elderly populations experiencing higher rates of severe illness and mortality [6, 7]. However, pediatric populations are susceptible to severe complications of COVID-19 including multisystem inflammatory syndrome and death, as well as morbidity from long-term COVID-19 symptoms [8].

At the start of the COVID-19 pandemic, a pediatric biorepository was established at Massachusetts General Hospital (MGH) in Boston, Massachusetts [9]. This biorepository collected, processed, and stored donated biospecimens including nasopharyngeal and oropharyngeal swabs, blood, sputum, stool, and urine. We hypothesized that among those approached for enrollment, due to normative development, school-age children (5–12 years) might be less likely to enroll in the biorepository or subsequently donate biospecimens compared to young children and infants (< 5 years) and adolescent and young adults (> 12 years). We also hypothesized that overall willingness to enroll may be higher than in pediatric biorepository studies conducted outside of a pandemic setting. We describe predictors of patient enrollment to a pediatric biorepository to identify strengths and gaps in COVID-19 research on pediatric biospecimens.

In this study conducted at the beginning of the first surge of SARS-CoV-2 in greater Boston, Massachusetts, 47% of all individuals approached were willing to enroll in a pediatric biorepository for COVID-19. Individuals living in areas at high risk of COVID-19, with symptoms at presentation, or who were admitted to the hospital were the most likely to enroll. These factors may have contributed to a higher perceived risk in individuals that ultimately motivated them to enroll in the biorepository. Even though enrollees tended to be older than non-enrollees, all age categories of interest were represented among biorepository enrollees. Enrollment sites were among the few available places where children could be evaluated in person and tested for COVID-19 during the early pandemic. While we hypothesized that enrollment would be higher than in pediatric biorepositories in non-pandemic settings, these data are lacking for pediatric biorepositories with as broad a focus. Few studies have examined demographics and factors associated with declining enrollment at the time of approach for enrollment, either for pediatric clinical trial research [13], or pediatric biorepositories [14‐17]. Furthermore, few existing studies on pediatric biorepositories enroll patients from a general pediatric population and rather focus on pediatric patients impacted by rare diseases such as congenital heart disease and cancer [13, 16, 18, 19]; enrollment rates in such biorepositories range from 55-97% [14, 18‐21]. To our knowledge, this is the first study of demographic and epidemiologic predictors of enrollment in a pediatric biorepository examining characteristics of pediatric patients themselves (rather than their parents/guardians) or conducted in a pandemic setting [14, 15, 22].

Previous studies within and outside the US context have noted that parents willing to enroll their children in a biorepository are more likely to be highly educated, have a higher income, and experience more trust and positive attitudes towards clinical research [14, 17, 23]. Parents are generally willing to enroll children in clinical trials [24‐26]. Parents agree to their children's participation of there is a higher perceived benefit to their children [15, 23]. Parents tend to overestimate the benefits of research on the well-being of their children and underestimate any risks in donating samples [26, 27]. While in the setting of this study, more deprived communities tended to be COVID-19 hotspots, it is notable that the community-level measurement of neighborhood socioeconomic status – Neighborhood Deprivation Index – did not predict enrollment. Participants and their parents may have had higher perceived risk in deprived neighborhoods, and therefore a tendency to agree to participate; furthermore, the establishment of community health research infrastructure antecedent to the pandemic may have facilitated research participation in these settings.

In the present study, parents were informed that donating samples would deepen our understanding of how COVID-19 impacts children. Although parents in the US and elsewhere may be less willing to enroll their children than themselves, parents’ beliefs related to their child’s enrollment generally mirror concerns they have for themselves [24, 27‐32]. Most people are aware of the potential risks of biorepository participation but do not feel concern about being harmed [27]. Overall, pre-pandemic, people have reported high levels of trust in public health and clinical research institutions [16, 28, 30]. Systemic or institutional trust is critical to address common concerns about biorepository enrollment, including biospecimen misuse and unacceptable research in the future (specifically human cloning), risk of identification or identity theft, insurance discrimination, and potential for corporate exploitation [28‐31]. Participants are comfortable donating if they feel they are adequately informed about how their biospecimens will be used. Those who feel the negative impact of biospecimens donation outweigh any positive impact tend to feel that people generally cannot be trusted, are most concerned about re-identification and have worries about information theft [30]. Concerns of data breaches and lack of confidentiality are deterrents to enrollment in biorepositories [33]. In certain studies, women and minorities are not as willing to donate their biospecimens, perhaps due to a historic lack of trustworthiness of institutions conducting clinical research (e.g., unconsented use of Henrietta Lacks’ cancer cells) [33‐35]. In contrast to prior reports from countries like the US or Australia, in which parents who are white or non-immigrants are most comfortable enrolling children into biorepositories [14, 35], in this study, in which 44% identified as Hispanic, we found that no one racial or ethnic group was more likely to enroll than another.

We hypothesized that school-age children would be least likely to provide nasopharyngeal swabs and blood. Parents are less willing to enroll their children when they are concerned about the physical pain or discomfort that their children may face, if their children are more seriously ill, or if they are concerned about their children’s privacy and confidentiality [13, 15, 16]. We found no differences by age or other factors regarding participants’ willingness to donate biospecimens, which suggests that efforts in this population should be most focused on enrollment itself rather than consenting for specific biospecimen provision.

This study had important limitations. First, by design, this analysis was conducted by chart review and electronic medical record download. We were, therefore, unable to explore reasons for declining biorepository enrollment at the time of being approached; while there are many studies detailing parental willingness to participate in a pediatric biorepository, few have examined motivations for declining enrollment at the time of enrollment [14, 19]. Given reports of high willingness to enroll, there may be important gaps between intention to enroll, enrollment completion, and biospecimen donation. Qualitative surveys of parental perceptions of clinical research institutions, corporate exploitation, religiosity, and data breaches would bolster the interpretation of our study findings. Second, we lacked data on individual-level parental highest level of education and socioeconomic status; to address this, we incorporated Neighborhood Deprivation Index. We also did not collect information on religiosity; in one study lack of religiosity has been associated with willingness to donate biospecimens [32]; another study noted that some religious individuals consider their tissue to be 'sacred' or part of their identity and found that higher religiosity made parents less willing to consent their children for biorepository participation [16]. Finally, our analysis was conducted in Massachusetts and so we were not able to investigate how willingness to consent and enroll differed by state.

Living in a COVID-19 hotspot, the presence of symptoms at presentation, and hospital admission predicted a higher likelihood of pediatric biorepository enrollment among children with suspected or confirmed COVID-19 infection. While overall enrollment appeared to be low compared to previous reports of pediatric biorepository enrollment, the population who consented to biorepository participation reflected those seeking care: children of all age and Neighborhood Deprivation Index categories were represented, as well as patients recording Hispanic ethnicity, who comprised a major part of the first surge in Boston [36]. Understanding whether enrollment is representative of the COVID-19 pandemic is critical to interpreting analyses conducted on donated specimens. Furthermore, understanding factors related to non-enrollment may also permit research to encourage enrollment among key demographics.