Recruitment, biospecimen, and data collection

Routine recruitment includes patients undergoing interventions at The Children’s Hospital at Westmead (Sydney, Australia); however, any patient with diagnosed CHD may be recruited. Neonates weighing less than 2 kgs and patients with a genetic syndrome known to be associated with CHD are excluded. Additionally, where probands have a family history of CHD or where they have a significant extracardiac abnormality, biological parents and additional family members may be recruited.

Approximately 70% of participant recruitment comes from outpatient appointments prior to cardiac surgery and ∼ 30% of participants are recruited as inpatients from the neonatal/paediatric ICUs or the cardiac ward (Supplementary Figure S1). During the consenting process, all participants agree to genomic testing and indefinite storage of their re-identifiable biospecimen and data in heart-related research. Further, they can indicate their preferences regarding: (1) result dissemination, including incidental findings; (2) data sharing and storage, including data linkage; and (3) involvement in future ethically approved heart-related research.

During recruitment, a detailed family history is obtained, including self-reported medical/health history and ethnicity (Table 1). Each participant’s CHD diagnosis is described using the European Paediatric Cardiac Code ¹⁸ , and medical records are reviewed to obtain additional health/medical data. All associated demographic, clinical, and family data as well as data relating to sample collection, processing, storage, and usage is contained within a purpose-built database. The database is a control centre for organising the inventory and keeping track of clinical and research genetic testing for each participant.

Staffing

Staffing of the Kids Heart BioBank requires a full-time research assistant, with oversight from a clinical lead, to identify and recruit potential participants, provide informed consent, facilitate sample collection and processing, and record associated medical/health data. This role also includes involvement in specific research projects, laboratory activities, and regular database auditing and maintenance. Kids Heart BioBank staffing also includes a genetic counsellor who provides counselling support and facilitates appropriate referrals to clinical services as required. Importantly, and in-line with ethics approval, none of the Kids Heart BioBank recruitment staff are involved in the clinical care of the patient.

Ethics and governance

All Kids Heart BioBank processes and activities are approved by the Sydney Children’s Hospital Network, Human Research Ethics Committee, and Research Governance. Ethics renewal is required every 5 years.

The Kids Heart BioBank is administered by the Governance Committee which consists of the Head of the Biobank and committee members with expertise in cardiology, developmental biology, genetics/genomics, scientific methods, genetic counselling, and ethical conduct. The Governance Committee is responsible for the scientific and ethical decision-making of the Kids Heart BioBank with recourse to the Human Research Ethics Committee and Research Governance as required.

Obtaining paediatric consent

The age at which a person becomes an adult in Australia is 18 years. In line with this, Kids Heart BioBank consent is sought from parents/guardians for most participants at our paediatric institute. However, from the age of 14 years, children/young adults may consent to their own participation with parental approval using age-appropriate participant information sheets and co-signing the consent form.

In line with biobanking regulations, the Kids Heart BioBank is required to seek approval for continued involvement in research when the participant reaches adulthood using an “opt out” approach. ^{Reference Rush, Battisti, Barton and Catchpoole19} To date, >1037 participants have been reconsented to the Kids Heart BioBank as adults. Notably, only 0.4% of reconsented participants have withdrawn their consent to date, highlighting the ongoing value of this resource to the adult CHD population.

Privacy and data security

Privacy is paramount, and Kids Heart BioBank protocol and processes have been established to minimise breaches in privacy, including the de-identification of biospecimens and all laboratory-based data. Further, database access by Kids Heart BioBank clinical and laboratory staff is separated, such that Kids Heart BioBank laboratory staff are unable to access any identifying information, including clinical and demographic data, and identify participants using their database generated code only. Kids Heart BioBank clinical staff can access all identifying data. All identifying data remain in the Kids Heart BioBank, and only de-identified biospecimens and/or clinical data are released to collaborators or external researchers. No biospecimens, clinical, or demographic data are released to third parties including the New South Wales or Australian Federal Police, except when enforced by court order.

Access to Kids Heart BioBank biospecimens

The Kids Heart BioBank considers applications for access to biospecimens and/or associated clinical data for both internal and external research studies and collaborations. Access is via the Kids Heart BioBank Access Policy, and all applications are considered by the Kids Heart BioBank Governance Committee. Access to Kids Heart BioBank biospecimens requires ethics approvals from the host institution where the research will be conducted. The application is reviewed by the Kids Heart BioBank Governance Committee where factors such as whether the proposed research aligns with the strategic and scientific aims of the Kids Heart BioBank and the impactful use of a limited resource are considered. Upon approval by the Kids Heart BioBank Governance Committee, the application is submitted to local ethics for final review and approval. Following local ethics approval, a material transfer agreement and other legal documents may be required and executed. For most access requests, the Head of the Kids Heart BioBank is considered a collaborator, in recognition of the foundational and ongoing work in maintaining the resource, oversight of the resource, and sample procurement.

Biobank funding and recruitment cost

The Kids Heart BioBank was established and initially supported through competitive grant funding from the National Heart Foundation of Australia. Ongoing biobanking costs, such as staffing and biospecimen management (including collection, processing, storage, and sample distribution), are supported by soft funding via donations, including from patients and their families. Biobanking processes that require funding are detailed in Supplementary Table S1. The total cost of recruiting, collecting, and storing a biospecimen is approximately AUD103 per participant (Supplementary Table S1), with the largest cost attributed to the salaried time taken to facilitate recruitment, participant data collation, and data entry. Additional costs include ongoing biospecimen storage, database maintenance, and data updates.

Kids Heart BioBank participation and consent rate

On average, the Kids Heart BioBank approaches ∼75% of eligible research participants presenting to The Children’s Hospital at Westmead for cardiac interventions as inpatient and outpatients. Reasons why eligible participants are not approached include (1) urgent/emergency surgery occurring outside of working hours (including on weekends) or with limited notification and no time to consent and (2) language or comprehension barriers. Eligible participants who are missed are often approached at subsequent cardiac procedures. Of those approached 94.1% of inpatients and 95.1% of outpatients consent to the Kids Heart BioBank. This consent rate is significantly higher than what is reported ^{Reference Brothers and Clayton20–Reference Menon, Ward and Gaboury22} and may be explained by the close alignment of biobanking processes with clinical care, including biospecimen collection at the time of intervention. It also likely reflects a strong desire and need by parents of children with CHD to understand the cause of their child’s heart condition, which is well described. ^{Reference Morrish, Smith and Enriquez5,Reference Blue, Kasparian, Sholler, Kirk and Winlaw23} Altruism is another factor, with many parents commenting that this research will hopefully benefit children with CHD in the future. ^{Reference Gao, Jiang, Feng, Guo, Hong and Liu21}

Of the ∼ 5% of eligible participants who do not consent to Kids Heart BioBank participation, reasons for non-consent include: (1) feeling overwhelmed; (2) needing more time to consider; (3) needing to consult with a partner not present during consent; and 4) concerns regarding blood collection at time of surgery (Supplementary Table S2) in line with previous reports. ^{Reference Menon, Ward and Gaboury22} The reasons for declining are similar between inpatients and outpatients (Supplementary Table S2); however, inpatients are more likely to decline due to “feeling overwhelmed” by the often-urgent cardiac care required. Interestingly, since 2022, there has been an increase in non-consent relating to concerns regarding blood loss during surgery; the reasons for this are not understood although under review.

Return of research results

There is little consensus as to what research results researchers are obliged to return to participants and best practice to facilitate this process. ^{Reference Vears, Minion and Roberts24} In Australia, there is currently no legal requirement for researchers to inform research participants of clinically actionable results. ^{Reference Tiller, Trainer, Campbell and Lacaze25} However, The National Statement on Ethical Conduct in Human Research ²⁶ requires researchers to have an ethically defensible plan to manage the disclosure or non-disclosure of genetic research results, including what results are returned to participants. Additionally, researchers are obligated to inform research participants that research results must be clinically confirmed at a nationally accredited clinical testing laboratory, prior to clinical use.

Most Kids Heart BioBank participants (99.4%) indicate that they would like to be informed of research results, compared with 54–88% of biobank participants reported in the literature. ^{Reference Vears, Minion and Roberts24} The strong preference in our cohort may be explained by access to genetic counselling and/or the genetics clinic, but it may also highlight parents’ desires for access to genetic testing in the absence of clinically available options, until recently.

During the Kids Heart BioBank consenting process, participants can indicate their preferences relating to the return of research results for clinically actionable variants related to CHD and incidental findings. Most Kids Heart BioBank participants (98.4%) want to be informed of clinically actionable incidental findings, described as incidental findings associated with preventable or treatable health conditions. All clinically actionable variants are reviewed by the Kids Heart BioBank Governance Committee with respect to clinical utility and relayed to research participants in consultation with their treating clinician. Research findings that are uninformative, of unknown significance and/or non-actionable incidental findings (i.e., are not preventable or treatable) are not returned to research participants.

In line with significant advances in the field in recent years, a dedicated CHD Genetics Clinic has been established at The Children’s Hospital at Westmead. The Kids Heart BioBank regularly refers patients with significant research findings to this service for clinical validation and subsequent clinical management (Supplementary Figure S1). Immediate and extended family members are also referred to this service where appropriate. Similarly, the CHD Genetics Clinic will refer patients with uninformative clinical genetic testing to the Kids Heart BioBank for inclusion in future research.

COVID-19 pandemic and impact on recruitment

During the COVID-19 pandemic of 2020–2022, biobanks worldwide were shut down or repurposed for COVID-19 research. ^{Reference Sims, Lawrence and Glazer27} Similarly, the COVID-19 pandemic had a significant effect on Kids Heart BioBank recruitment and processes. The number of eligible research participants approached decreased from ∼ 75 to 40% in 2020 following cessation of elective cardiac surgery. In 2021, the number of eligible participants approached decreased further to 25% due to a 107-day lockdown in New South Wales, Australia. Further, throughout this time, single parent attendance of children presenting to the hospital was enforced.

As of January 2022, the number of eligible Kids Heart BioBank participants approached has returned to pre-pandemic levels (∼74%). Interestingly, non-consent has increased from 5–11/year prior to the pandemic to ∼ 30/year in 2022, possibly reflecting continued societal stress post-pandemic and/or decreased interest in non-essential health activities.

CHD research

The Kids Heart BioBank has made significant and valuable contributions to the field of CHD genetics. Specific research outputs include over 30 publications that have resulted from in-house as well as large national and international collaborations (Figure 2, Supplementary Table S4). More recently established linkages to national and state-based administrative health, clinical, and registry databases provide important additional research opportunities. The significant impact likely relates to the focused nature of the Kids Heart BioBank, the co-location within the clinical programme and clinical workflows, the establishment of a multidisciplinary consortium including computer scientists and researchers, and its identifiable role in CHD research.

Figure 2. Contributions of the Kids Heart BioBank to CHD research over time. International/national collaborations and resulting peer-reviewed publications supported by Kids Heart BioBank participants and/or associated data are listed. n = number of collaborations/publications using Kids Heart BioBank participants and/or associated data.

Since its establishment 20 years ago, the Kids Heart BioBank has contributed to many significant advances in the field of CHD genetics; from identifying new disease genes using single gene screening ^{Reference Butler, Esposito and Blue28,Reference Kirk, Sunde and Costa29} , identifying risk loci in the largest genome-wide association studies in CHD at the time ^{Reference Skoric-Milosavljevic, Tadros and Bosada17,Reference Cordell, Bentham and Topf30,Reference Soemedi, Topf and Wilson31} , to the application of genomic technologies. ^{Reference Blue, Kirk and Giannoulatou12–Reference Szot, Cuny and Blue14,Reference Blue, Humphreys and Szot32,Reference Blue, Mekel and Das33} The Kids Heart BioBank has also contributed to important and timely psychosocial research related to advances in the field, including highlighting the value of genetic counselling provision for CHD patients and families. ^{Reference Blue, Kasparian, Sholler, Kirk and Winlaw23,Reference Hunt, Hilton and Verrall34} Further, Kids Heart BioBank participant biospecimens have supported other functional genomics research, including studies to validate variant pathogenicity ^{Reference Chapman, Moreau and P.E.35} and have indirectly facilitated the development of new protocols and methodologies that are used by researchers worldwide. ^{Reference Bosman, Edel, Blue, Dilley, Harvey and Winlaw36–Reference Fonoudi, Ansari and Abbasalizadeh38} Research findings enabled by the Kids Heart BioBank, together with those of other researchers, as well as our experiences with patients and research participants have also been summarised in key reviews. ^{Reference Morrish, Smith and Enriquez5,Reference Blue, Kirk and Giannoulatou9}

Supporting patient care

The most common questions asked by patients with CHD and their families are “why did this happen?” and “what are the chances of it happening again?” ^{Reference Blue, Kirk, Sholler, Harvey and Winlaw3,Reference Blue, Kasparian, Sholler, Kirk and Winlaw23} Finding an answer to these questions triggered the development of the Kids Heart BioBank and underpins its associated research. In Australia, until recently, genetic testing for patients and families affected by CHD was only available via research pathways. As such, for over a decade, the Kids Heart BioBank has provided an important avenue for access to genetic testing and counselling for patients and families who would otherwise not have had access to these services.

To date, over two-thirds (64.1%) of Kids Heart BioBank probands have participated in at least one research study. Of the Kids Heart BioBank participants who have undergone research genomic testing to identify the genetic cause of their CHD, 28.9% had a pathogenic or likely pathogenic variant identified according to American College of Medical Genetics and Genomics guidelines at the time ^{Reference Richards, Aziz and Bale39} (Table 2, and Supplementary Table S3). Kids Heart BioBank participants with an affected first-degree relative (i.e., a family history of CHD) and participants with extracardiac anomalies had a higher chance of being identified as carrying a pathogenic or likely pathogenic variant (38.1% and 35.3%, respectively), compared with participants with sporadic CHD (13.5%).

Table 2. Research genetic testing outcomes in Kids Heart BioBank probands. Genetic testing technologies utilised include a purpose-designed CHD gene panel, exome, and genome sequencing

Note: Variant classifications reflect published literature and research reports at the time and have not been re-evaluated in accordance with updated American College of Medical Genetics and Genomics (ACMG) guidelines.

P = pathogenic; LP = likely pathogenic; VUS = variant of uncertain significance.

* Proportion of probands as a percentage of proband category.

These findings are largely in keeping with current literature on CHD diagnostic yields across the various CHD presentations which currently suggest an approximate diagnostic yield of 30–40% in patients with familial disease and those with extracardiac anomalies. ^{Reference Morrish, Smith and Enriquez5,Reference Wilde, Semsarian and Marquez8} Some of the yields in the Kids Heart BioBank are inflated, which is likely reflective of selection bias associated with individual research projects.

Importantly, the findings and diagnoses made above occurred during a time when most patients with CHD and their families did not have access to genetic testing. The clinical utility and value of research to patients and their families cannot be underestimated with many participants using clinically validated research findings to provide reproductive options, including preimplantation genetic diagnosis. Further, research findings have had direct clinical utility for many patients and their families in terms of the ongoing management of their heart defects and the identification of heart defects in previously undiagnosed family members.

In addition to the direct benefits to patients of our research programme, the benefit to CHD patients has also been evidenced more broadly. Novel technologies, including genomic technologies, were first adopted in a research capacity, with findings from our research and that of others leading to the development of clinical genetic testing pathways for this patient group. In Australia, government-funded clinical genetic testing options are now available for patients and families with familial forms of disease and in patients with extracardiac anomalies. For patients with sporadic and isolated disease, the Kids Heart BioBank continues to provide an avenue for research genetic testing, following limited clinical options. The Kids Heart BioBank regularly receives research referrals from Clinical Genetics services for sporadic CHD and for cases with uninformative clinical genetic testing. Similarly, the Kids Heart BioBank, which is intimately linked in with clinical processes, facilitates the appropriate referral of patients and families who are unaware of the clinical genetic testing options now available to them, further demonstrating the important reciprocal relationship between research and clinical care for this patient group.