Overcoming challenges in the acquisition of biospecimens for rare diseases

Abstract

High-quality biospecimens are vital to furthering our understanding of human disease. Biospecimen collections for rare diseases pose unique challenges, and collaboration is often necessary for success. Several initiatives and tools have been developed to facilitate the collection of high-quality biospecimens and increase collaboration for biospecimen users. As science and technology advance, the research community must continue to develop tools and solutions to improve Biospecimen Science, advance research, and facilitate collaboration, while keeping pace with evolving scientific and ethical considerations.

Keywords::

• biorepositories
• biospecimen science
• confidentiality
• rare disease

1. Introduction

Biospecimens are the human tissues and bodily fluids that form the foundation for research efforts as well as clinical diagnosis of disease. Procuring high-quality biospecimens with associated clinical data is vital for furthering our understanding of human disease. The availability of such biospecimens for research can lead to significant advances in rare disease research, and collaboration is often necessary for collection. For example, blood biospecimens to enable research in cardio-facio-cutaneous syndrome (CFC) were collected with the patient advocacy group, CFC International. Such collections were integral to research that implicated the Ras/mitogen-activated protein kinase (MAPK) pathway in the development of CFC [1]. CFC is a member of the RASopathies family, a family of medical genetic conditions caused by mutation in the MAPK pathway, including neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, CFC and Legius syndrome [1]. This pathway has been intensely studied in additional diseases including cancer, and is an attractive therapeutic target. Despite the clear need to utilize biospecimens in disease research, obtaining high-quality biospecimens remains a challenge, especially for rare diseases and collaboration may be necessary.

Rare disease is defined as affecting < 200,000 individuals at any time in the USA, or < 1 in 2000 in Europe [2]. There are an estimated 6000 – 8000 rare diseases, with some affecting a small number of individuals and others affecting tens of thousands [2]. Approximately 80% of rare diseases have genetic underpinnings, and 50% affect children [2]. It is essential to improve the availability of biospecimens to advance research on rare diseases. Rare disease research faces many of the same biospecimen challenges encountered in other human disease research, with additional, unique challenges due to the low number and dispersed location of prospective research participants. This commentary focuses on some of the scientific, information and social challenges in biospecimen acquisition for research, and newly developed programs that promise to improve this complex situation.

2. Biospecimen Science

Biospecimen quality is of critical importance for all sample collections. However, procedures for biospecimen collection, processing and storage vary between clinical settings and these pre-analytical variations can lead to a wide variation in quality of specimens and data. Analysis of biospecimens with unknown and/or poor quality can lead to inaccurate and potentially misleading research results, depending on the downstream assay for which the samples are used. For example, changes in specific transcript levels can be falsely identified as disease-related, when in reality the changes may relate more to pre-analytical factors such as different surgical ischemia times [3,4] or types of collection tube [5,6]. Pre-analytical factors can include pre-acquisition factors such as presence of antibiotics or other drugs, type and duration of anesthesia and time of arterial clamp time, as well as post-acquisition factors such as time and temperature before stabilization, type of and time in fixative, and aliquot size. Identifying markers of biospecimen quality has proven to be difficult, as effects are often specific to the pre-analytical factor(s) encountered, the analyte of interest, and the downstream assay used.

The term Biospecimen Science has been coined to describe the field of study that examines biospecimen pre-analytical factors and their effects on molecular integrity. Two dedicated initiatives have been launched to systematically investigate Biospecimen Science: the US National Cancer Institute's (NCI) Biospecimen Research Network program (BRN) [7] and the European Union's Standardisation and Improvement of Generic Pre-Analytical Tools and Procedures for in vitro Diagnostics (SPIDIA) Consortium [8]. Investigators in both programs are producing research data to support evidence-based guidelines for pre-analytical procedures, including biospecimen collection, handling, transportation, processing and storage. The BRN also maintains a Biospecimen Science literature database, the Biospecimen Research Database (BRD) (https://brd.nci.nih.gov/), which catalogs expert curations of < 2000 published studies related to variation introduced by pre-analytical factors. BRN and SPIDIA research, supplemented by BRD research summaries and expert input, will form the scientific basis for evidence-based biospecimen best practices, building on the NCI Best Practices for Biospecimen Resources [9] and the International Society for Biological and Environmental Repositories (ISBER) best practices for Repositories [10].

Due to the many biospecimen collection, processing and storage procedures in use, it would be ideal for biospecimens to be thoroughly annotated with every piece of relevant data in order to support future users who may have no connections to or understanding of the collection protocols that were utilized for a stored biospecimen. Two initiatives are underway to encourage the recording of biospecimen pre-analytical factors. These include Biospecimen Reporting for Improved Study Quality (BRISQ) and Standard PRE-analytical Coding (SPREC) for biospecimens. The NCI Biorepositories and Biospecimen Research Branch (BBRB), formerly known as OBBR) developed BRISQ to guide researchers and publishers of scientific literature in the proper inclusion and interpretation of information about the source and handling of the biospecimens that form the basis of scientific manuscripts [11]. The ISBER Biospecimen Science Working Group developed SPREC to help biobankers and researchers capture essential biospecimen protocol information in order to provide information to researchers about the conditions under which research biospecimens were collected and thus provide some indication of the relative biomolecular quality of samples [12].

3. Tools to enable collaboration

One of the major challenges of rare disease research is that affected individuals are often spread out across the world, and very few investigators have the resources to develop a large cohort. To build an adequately powered cohort requires collaboration with other investigators and institutions, as well as with patient advocacy organizations. Without collaboration, rare disease collections are often fragmented and inadequately powered. Additionally, there may be significant redundancy between cohorts, if individuals donate samples to more than one research collection. One solution to this problem is a GUID, or global unique identifier, a code that can be used to link data across registries, biorepositories and other studies without exposing personally identifiable information. A GUID can be generated for each participant based on information available on his or her birth certificate (e.g., first, middle and last name, birth date, birth city, state and country). GUIDS are currently implemented by the National Autism Research Database (NDAR) [13].

As previously noted, rare disease specimens can be very difficult to collect. How does one interested in conducting rare disease research locate and access biospecimens? Rare disease biospecimens, as with the majority of all human biospecimens, are often stored in redundant, siloed, fragmented collections with variable associated clinical and biospecimen collection data. Compounding the problem, these samples are geographically dispersed and difficult to locate. Rare-disease HUB (RD-HUB), developed and managed by the National Institutes of Health's Office of Rare Diseases Research (ORDR), provides a searchable database to help researchers find biospecimens collected and stored by domestic and international biorepositories [14]. Both rare and common diseases are included in the resource. RD-HUB can assist investigators and others locate and identify specific biospecimens, and facilitate sharing of material and information. RD-HUB also builds awareness of biorepositories and specific biospecimen collections. RD-HUB includes a convenient list of fields required and frequently asked questions for entering biorepository data.

The NCI Specimen Resource Locator is another resource that can help researchers locate human specimens (e.g., tissue, serum, DNA/RNA, other specimens) for cancer research, including biospecimens from research participants with rare cancers [15]. This resource includes tissue banks and tissue procurement systems with access to normal, benign, precancerous and cancerous human tissue from a variety of organs. Information is displayed for each resource, including contact information, availability and access requirements, fees and links to resource web sites. If there is no direct match, a request can be emailed to the NCI Tissue Expediter, a scientist who can rapidly match investigators with appropriate tissue and data resources and help to identify potential research collaborators.

4. Maintaining the confidentiality of research participants

When participants in a research study donate biospecimens, there is a traditional and foundational element of trust between research participants and research investigators to maintain confidentiality of the research participant. Such confidentiality in biobanking is often secured through the coding of research biospecimens such that only a very limited number of researchers have access to specific information that can identify individual research participants by name, birth date and so on. The principles underlying this approach were established by numerous US and international policies [16-18] and have been an essential element of Institutional Review Board approvals for donation of biospecimens and good biobanking practices.

For research participants with rare diseases, it has long been a concern that, despite the implementation of formal measures to maintain confidentiality, an individual or group with a rare disease may inadvertently become identified as being part of a research study. Further, new concerns have come to light that suggest that through analysis of the data resulting from molecular research on a biospecimen, a research participant can be identified amongst a group of similar participants [19]. These concerns have come from advances in bioinformatics technologies, and studies have been performed that convincingly demonstrate that such identification is possible. Such identification has been demonstrated only on a theoretical basis and no specific harms to individuals have been associated with such approaches. Nevertheless, these studies have initiated an important conversation within the research and regulatory communities to determine whether new approaches to identifiability are needed [19]. For advocates of research in rare diseases, concerns about identifiability may be countered by the urgent need to move forward with the research mission while solutions to identifiability concerns are in progress.

5. Conclusion

High-quality biospecimens are vital to furthering our understanding of human disease. Initiatives such as BRN and SPIDIA, and tools, including BRISQ and SPREC can help to facilitate the collection of high-quality biospecimens. Biospecimen collections for rare diseases pose unique challenges, and collaboration is often necessary for success. RD-HUB and the NCI Biospecimen Locator have been developed to increase collaboration by assisting researchers in locating biospecimens. As science and technology advance, there are increasing concerns about the continued protection of participants' confidentiality, especially in small communities including rare diseases. The research community must navigate this complex landscape by continuing to develop tools and solutions to improve research and collaboration, while keeping pace with evolving scientific and ethical considerations.

Acknowledgements

The authors are grateful to Kelly Engel for contributing key references in Biospecimen Science.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.