Biobanking

Background

Biobanks may be established for nonresearch purposes, such as diagnostic, therapeutic, treatment, forensic, transplantation, and transfusion, or for research purposes as part of epidemiologic studies and clinical trials. Biobank planning is essential for biospecimen integrity in support of such research, but also for the establishment, governance, management, operation, access, use, sustainability, and discontinuation of biobanks.

Content

We focus on best practices procedures for collection, processing, storage, and retrieval of biospecimens with regard to downstream analyses for blood, urine, and saliva. Security measures, disaster planning, quality management, accreditation and certification, staff education, chain-of-custody, annotation of data, cost, and sustainability issues are reviewed. Adoption of various internal and external standards is discussed. Ethical, legal, and social issues, as well as administrative issues regarding governance, ownership, stewardship, and access criteria are discussed.

Rationale and objectives for biobanking

The rationale for initiating biobank collections may be research, diagnostic, therapeutic, transplantation, transfusion, quality assurance, forensic, or archeologic studies (which may be used for exhibits, education, and research). Initiators may be from academic, hospital, governmental, or industrial organizations.

The objectives of biobanks are many and depend on the nature of the intended research. Many biobanks collect data for future research projects for which the aims and technologies are not necessarily well developed at the time when samples and accompanying data are collected. For the biobanks which are primarily storage warehouses and not engaged in research, the objective may simply be to maintain the highest-quality samples possible. In clinical and research biobanks, the objectives may be omics-biomarker research combined with clinical data to predict individual predisposition of disease, target prevention, and personalize treatment (personalized or precision medicine) tailored to each individual person. ^, For biobanks focused on quality assurance, the objective may be to use the material for developing or optimizing new diagnostic methods. The objective of therapeutic biobanks is to store viable tissue from donors for future recipients (i.e., semen or oocytes). The objective of forensic biobanks is to store the biological material from which the DNA profiles were analyzed, for documentation and possible testing for legal purposes. For the archeologic collections, the objectives may be the development of exhibits, educational material, and research in evolutionary biology and anthropology.

Types and use of biobanks

Biobanks may be classified according to the funding source, the ownership, the location, the recruitment strategy, the biospecimen type, the administration, the users, the purpose, or membership in a network ( Table 11.1 ). ^, According to surveys of US and European biobanks, most biobanks are disease-specific compared to general population collections.

Human biobanking takes place in the pharmaceutical industry, commercial labs, government facilities, hospitals, and academia. Biobanks are central tools in basic research, genetic epidemiologic studies, and clinical trials and the results are used in translational research and precision medicine.

A biobank may store samples from other biobanks, from many basic or translational research projects, and from clinical settings as well, and is thus a storage facility. Research biobanks may process and store samples from specific phenotypes and patients with a specific disease (i.e., cases) and in addition samples from representative disease-free controls from the underlying population, or samples from a general population base. General population studies may collect biospecimens on a single individual basis or on a family basis. Both case-specific biobanks and general population biobanks may have representative samples from only specific age groups (e.g., children vs. adults) or from any age range. Case-specific biobanks are useful for diagnosis, disease stratification, and prognostic purposes. Clinical biobanks may store samples from cases with a given disease, but are primarily organized for clinical purposes, usually as part of a diagnostic process. Some clinical biobanks are also research biobanks, where the participants have provided informed consent for future use of diagnostic samples for research purposes. Both clinical and commercial biobanks may store samples from volunteers for treatment purposes (stem cells, transplant organs and tissues, oocytes). Depending on the type of biobank, different regulations and accreditation procedures exist.

Preanalytical variability

The term preanalytical is defined as anything that comes before the analysis phase of a biospecimen sample (see also Chapter 5 ). Thus in biobanking preanalytical handling is basically all processes that precede the analysis of a biospecimen after it is collected from a donor or removed from storage. Preanalytical variables are factors that affect the integrity of the biospecimens, and later the results of analyses. Assessing and controlling the preanalytical handling of biospecimens is fundamental for the integrity and optimal future use of biospecimens. ^, Biobanking involves the collection, processing, transport, storage (biopreservation), and retrieval of biospecimens. Evidence-based practices are critical to the future of biobanking, but more research is needed. Many factors influence the analytical results in clinical biochemistry, that is, preanalytical biological or environmental variability, preanalytical technical variability, analytical variability, and postanalytical variability (see At a Glance: Biobanking). Most errors in a clinical chemistry lab are due to preanalytical errors ^, and may result in inaccurate test results or systematic biases. The most common preanalytical errors occur in the ordering or collection phase. Preanalytical variables can introduce in vitro modifications, either systematically or randomly, which can adversely affect laboratory results.

Ordering, collecting, and receiving biospecimens

The collection of human biospecimens is a part of the biobanking process that cannot easily be automated and depends on many factors, such as availability of biospecimens, staff, participants, management, and logistics ( Box 11.1 ). Collecting biospecimens in cohort studies is a balance between biospecimen quantity and type, accrual rate and number, location, costs, transport logistics, and storage requirements. The resulting participation rate may depend on what level of cooperation is reasonable to request from a participant. The collection of biospecimens may be invasive (e.g., blood), less-invasive (e.g., dried blood spot [DBS]), or noninvasive (e.g., urine or saliva). Blood and urine are biospecimens commonly collected for clinical analyses. Less-invasive and noninvasive methods minimize use of valuable blood samples, and may lead to an increased sample size of the study population owing to their reduced costs, ease of collection without specialized staff, and willingness of participants to donate ( Table 11.2 and Box 11.2 ).

In a clinical chemistry laboratory, preanalytical variables related to ordering or receiving biospecimens may impact the quantity or quality of biospecimens (e.g., missed, incorrect, or duplicate collection, data entry error, incorrect patient or collector ID, insufficient sample, diluted sample, improper labeling, lost biospecimens) ( Table 11.3 ). If biospecimens are obtained without consent, with a lost consent, or a restricted consent, then their value may be limited.

Biological and environmental factors may also affect downstream analyses ( Box 11.3 ). The total variability of these factors may impact the concentrations of analytes. Smoking may increase red and white blood cell indices. ^, The participants’ position during blood collection may affect many molecules’ concentrations, which increase from supine, to sitting, to standing position, although the latter position is discouraged. See Chapter 5 for further discussion on this topic. Twenty-four-hour variation may be seen in many chemistry analytes, with peak and low values at different times of the day. Marked metabolic and hormonal changes occur after food ingestion. The postprandial response varies according to factors such as eating behavior, food composition, fasting duration, time of day, chronic and acute smoking history, and coffee and alcohol consumption. Some biological factors can be controlled in studies by requiring certain conditions for participant inclusion, for example, fasting/nonfasting, abstaining from smoking and strenuous exercise hours before collection (see Box 11.3 ). Environmental factors include geographic location, altitude, inside or outside temperature, season, humidity, and moisture. ^{, ,} During summer vitamin D concentrations are higher than in winter, and in more sunny geographical locations individuals have higher vitamin D values than in less sunny locations. Direct sunlight may affect concentrations of bilirubin, porphyrins, and vitamin A. The total variability of these factors may impact concentrations of analytes. For the measurement of medication concentrations and hormones, the timing of collection is especially important. Thus these factors should be standardized, documented, and taken into consideration when interpreting results or comparing or pooling the results of multiple studies. Collection of repeat samples from the same individual taken a few days apart may attenuate the effects of preanalytical and analytical variation. Serial measurements may also be taken with longer time intervals between, to measure changes or effects of intervention over time.

All biospecimens should be treated as biohazards and all processes involving biospecimens should adhere to principles of general laboratory safety.

Processing of biospecimens

Automated systems for processing samples incorporate barcode reading of primary tubes (collection tubes), decapping, fractionating, aliquoting into predefined secondary tubes or plates, and transferring of labels onto secondary tubes. The automated systems should have complete sample tracking capability. Benefits of automated fractionation systems include fewer errors in sample handling and prevention of endurance related injuries due to repetitive work actions. Such systems are operator independent and ensure proper sample tracking. In laboratories with low throughput or less financial resources, manual handling may be needed, but this approach increases the risk of errors. Multiple aliquots should be created at the beginning of processing a biospecimen rather than delayed until the specific assay is conducted, as repeated freeze-thaw cycles may be detrimental in some cases (e.g., RNA). ^, A study confirmed the validity and reliability of a high-throughput, high-density, low-volume biobank sample processing solution for blood fractionation and archiving biospecimens utilizing the 384 aliquoting format sample storage tube system. A study of high-density scaling allowed for reproducible aliquoting and processing of 70-μL volumes of blood. With this approach the authors introduced the principle of single-use only for samples, circumventing multiple freezing and thawing cycles.

Storage of biospecimens

Ideally, a “freeze-thaw stable” fluid biospecimen is not affected by thermal, mechanical, or chemical stress. Thus the goal in storage of biospecimens is to minimize or halt these detrimental processes. Storage encompasses both short-term and long-term storage of biospecimens, depending on their planned future use. Biospecimens contain degradative molecules (e.g., proteases, lipases, nucleases). Long-term storage may result in aggregation, precipitation, or biochemical degradation of proteins (altering both structure and activity); ice damage; dehydration and increase in salt concentration resulting in osmotic damage; formation of water crystals; recrystallization after thawing; and toxicity from substances that are added to the biospecimens in the freezing state (cryoprotectants) or in the drying state (lyoprotectants) in order to protect the active ingredients. These changes may cause the real biological variations to disappear. There is a considerable variation among biomarkers in stability and recovery; therefore different storage conditions may apply depending on the downstream analyses. Preanalytical variables for long-term storage are listed in Table 11.3 . Freeze-thaw cycles are a major concern, and may happen unintentionally during transport of frozen samples or freezer failure, or intentionally because the biospecimens are thawed for analyses and then refrozen.

In order to mitigate possible freeze-thaw cycle problems, controlled rate freezing and thawing methodology may be employed. These technologies are used especially in the case of cell preservation. For example, in 2019, Baboo et al. studied the effects of various rates of controlled freezing and thawing on the viability of human cryopreserved T cells.

It is advised to perform pilot studies and to carefully search the literature before measuring biomarkers on stored biospecimens. It is also important to have some biospecimens available only for quality control purposes, on which the same biomarkers are measured in fresh biospecimens repeatedly on a regular annual basis to monitor any critical changes ( Box 11.4 ). Standard protocols are necessary for reproducible and reliable results.