Overview

Databases are both the result and the instrument of research. From the earliest times, assembling collections of samples and stories was essential for any research project. The results of research feeding back into the libraries and collections create a positive feedback in the accumulation of knowledge limited only by the technological platform for storage and retrieval of information. The modern times did not change the principle but further emphasized it with the advent of computers, mass information storage, and high-throughput research instrumentation. Modern biomedical databases may vary in size, specialization, and type of access but with a few exceptions are voluminous and include complex data from multiple sources. Arguably, the first integrated database of the population scale was initiated in Iceland when Decode Genetics started in 1996 [1]. This new generation of integrated biomedical databases incorporates both phenotype (medical records, clinical studies, etc.) and genotype (variation screening at first, now increasingly shifting to whole exome and whole genome sequencing [2, 3]). The project started by Decode has generated one of the best resources for discovery in biomedical sciences and inspired development of multiple populational and national genomics projects, also feeding into integrated databases. Genomics England [4], Human Longevity [5], All of US (formerly known as Precision Medicine Initiative) [6], China’s Precision Medicine Initiative [7], Korean Reference Genome Project [8], Saudi Human Genome Program [9], and Qatar Genome [10] programs are just a few recent examples of active large-scale projects generating enormous databases of complex biomedical information. Large-scale population genomics projects proliferating in the second decade of the twenty-first century show enormous diversity in goals and strategies. The Icelandic genome program has evolved from the largest population genetics study of the time and has primary objectives in advancing biomedical research. China’s Precision Medicine Initiative is one of the most ambitious programs with an aim to sequence 100 million whole human genomes by 2030. The objective is to improve disease diagnosis, develop targeted treatments, and provide better wellness regimes. Genomics England is an augmented (100,000) research cohort study that implies sampling of the most common diseases and reflecting the genetic diversity of the population in Great Britain. The All of Us project has similar objectives and aims to collect a sufficiently large cohort (1,000,000). The numbers alone have a great ameliorating effect on statistical power of association studies. Deep phenotyping and follow-up sampling in All of Us are aiming to develop the new level of precision in diagnostic and treatment of multiple diseases. The declared aims of the Human Longevity project are even more focused on a specific range of age-associated diseases. To achieve its goals, Human Longevity plans to recruit about 1,000,000 donors. The Saudi Human Genome Program has a very different focus; it aims to develop effective methods and facilities for early diagnostics and treatment of heritable diseases. Such goal does not require the genome sequencing effort on the same scale as All of Us or Genomics England. The program implements only a small number of whole genome sequencing and up to 100,000 whole exome sequencing to collect the data reflecting local genetic variation and design a microarray chip for cost-effective mass neonatal screening. In contrast, the national genome program in Kuwait requires complete sampling of the entire population including nationals and non-citizen residents because the principal goal, according to the recently adopted DNA Law [11], is to counteract terrorist activity by precise unequivocal identification of every human being. The Qatar Genome Programme (QGP) aims to integrate genome sequencing information of all Qatari nationals with electronic medical records (EMRs) and results of clinical studies to provide quick and precise personalized diagnostic and treatment of diseases. The goal is to provide a solid basis for the biomedical research in the country.

These biomedical databases are often viewed as a platform for regional and worldwide collaborative research projects. Both the construction of these resources and serving them to a growing research community (national and international) present a significant challenge toward preserving the privacy of the participants.

Particularities of genomic data

Paper outline

At each stage, we discuss current practices and challenges, as well as contemporary research efforts, with a particular interest in data sharing for research purposes [17]. We provide examples from a diversity of large-scale population sequencing projects and reflect on their scope and data governance models.

Note that the above division is simplistic as the different stages are not mutually exclusive; however, it makes for a simpler and more organized presentation of the different ideas.

Where to store the data?

Data storage presents a significant technological challenge for many large-scale genome projects. The total volume of deep whole genome sequencing (WGS) with raw read, aligned, and variant calling data can reach 0.5 TB per genome. Phenotyping, imaging, and omics data add additional volume. The specific number may vary widely depending on the types of data collected. Questionnaires and physiological tests, even as comprehensive as those conducted by Qatar Biobank, when collecting samples for the Genome Sequencing Program, add only a small percent to the total volume. Digital images can potentially add large volumes on the same scale as genome sequencing (i.e., on TB scale). However, the real imaging data associated with a particular sample donor in current projects is relatively small and does not exceed gigabyte (GB) scale. Omics data (such as gene expression, methylation, or metabolomics) can also be as large as genome sequencing data. Some of such data is produced using similar next-generation sequencing techniques that result in the same volumes of raw data, which can be stored to reproduce the downstream analysis. Multiple tissue samples can be taken for omics analysis from different organs of the same donor, at different times or in different disease states. This potentially can multiply the volume of data by as many times as more samples are taken. However, at this time, this kind of data is rarely added in significant amounts due to the high costs of high-throughput methods. WGS data remains the most voluminous part of genomic databases. With reserve copy and redundancy, the overall data volume requires petabytes of storage space even for relatively small population studies with tens of thousands of samples. Data compression and selective saving of key data files (while other types of data can be reproduced from initial and intermediate data) can reduce the requirements. Nevertheless, the overall data storage demand in population sequencing is enormous. In the QGP example, it has been originally estimated as 300 PB. The challenge is further compounded by requirement of fast access to individual data files, high-throughput access to multiple genomes in research cohort studies, and long-term storage keeping the data safe and actively used for decades ahead. On the other hand, the price of storage has a hard ceiling dictated by the progress in sequencing technology: the price for data storage per gigabyte should not exceed (and better be significantly lower than) the price of sequencing of the same data from a stored sample. Such demands and limitations make engineering the data storage facility extremely challenging.

In general, the data can be outsourced to a cloud provider or stored on a private—locally managed—cloud. The former approach obscures the complexity of technology but demands highly developed broadband network infrastructure and limits the control over data security and access performance. The overall performance of a cloud-based data storage solution in a large-scale project is gated by the availability of broadband infrastructure. Nevertheless, when local conditions offer adequate answers to security and broadband infrastructure challenges, cloud solution can be very attractive. Genomics England with a goal of 100,000 WGS and full complement of phenotype data is the most brilliant example [25]. The latter approach can be more expensive in terms of engineering, capital expenses, and running costs. In the QGP example, the storage is engineered as a complex solution that involves multiple redundancy and multi-tier storage on different information carriers ranging from flash drives to tape libraries. However, the storage service is provided in a form of a single name space private cloud (see overview in Fig. 1).

In other examples of local storage solution for large-scale genomic and biomedical data, the technical details of storage architecture are rarely detailed and rely on the local policies of the data center for data integrity, security, and safety. Examples of such projects include the Estonian Genome Project and Saudi Human Genome Program [26, 27].

How to store the data?

To minimize the risk of harm, most research platforms store de-identified clinical and biobank data while retaining the link between both data sources (the de-identified EMR data and the biobank data). This can be achieved by applying the following two operations:

1. 1.

   The first operation (known as pseudonymization) identifies a stable and unique identifier(s) (such as Social Security numbers and national IDs) that is included in both data sources and replaces it with a unique random ID or pseudonym (refer to Fig. 2). The pseudonym can be obtained by encrypting or hashing one or several identifiers. Decode genetics uses a symmetric encryption algorithm (TwoFish) to convert the Social Security number (SSN) to an alphabet-derived string. VGER hashes the medical record number using the public hashing algorithm SHA-512.

    
2. 2.

   The second operation removes all uniquely identifying information (such as names, record number, and emails) from the structured data and masks all unique identifiers from the unstructured data (such as doctors’ notes), (refer to Table 1 for examples of unique identifiers). Additional fields can be also removed from the data for added privacy; the VGER project, as an example, removes all geographic information smaller than a state and all elements of dates (except year) directly related to the individual (such as date of birth and date of death) and shifts all hospital visit dates by a random value between 1 and 364 days (the shift being the same across the record of the same patient to preserve temporal analysis).

    

Uniquely identifying fields	Remarks
National ID (or SSN)
Name	Names of patients and caregivers
Email
Source ID	Hospital/Biobank-assigned IDs
Passport number
Exact address

Privacy breaches can occur if the data is leaked to an unauthorized party. Such leakage can happen if (i) the stored data is hacked/handled recklessly or if it is (ii) shared with a pretentious/irresponsible third party. After applying the pseudonymization process, the data remains vulnerable to de-identification attacks (in other words, although de-identification makes re-identification harder, it does not eliminate the risk). Thus, a strong security layer is needed to ensure that unauthorized individuals cannot access/modify the data. Encryption alone is not an adequate security solution, particularly for genomic data. As explained in [28], encryption schemes gradually weaken in the long run, while the information hidden inside a genome remains stable and is better interpreted with time. Thus, if encrypted genomes are available to an unauthorized third party, the party will be able to decrypt it with time (40–50 years).

Commercial cloud providers (such as IBM and Amazon) claim to employ foolproof security, but their models are not shared publicly and thus cannot be learned and evaluated. Security of the privately held infrastructure and private clouds depends on the proficiency of system administrators and security specialists employed by the custodian organization. In some cases, like the Qatar Genome Programme, geographic location and state-regulated data access may provide additional protective layer against sporadic attacks and “social engineering” hacks. However, the ability of genomic data storage to withstand a determined and competent invasion is yet to be tested.

Access mechanisms and privacy

Data sharing mechanisms can be categorized into two broad categories: open-access and controlled-access. While both were widely used for regulating genomic data sharing, open-access datasets have been used in many more studies per year [29]. Open-access models either operate under a mandate from participants (who want to publish their genomic data in public platforms) or under the assumption that the shared data is de-identified and possibly aggregated [30]. However, as demonstrated by multiple recent studies, the risk of re-identification is strongly present. It was shown, in multiple independent studies, that it is possible to learn the identities of people who participate in research studies by matching their data with publicly available data [31]. In a recent study [32], the authors showed that they can infer the identity of 50 anonymous male subjects whose Y-chromosome has been sequenced as part of the 1000 Genomes Project. The researchers were not only able to discover the identities of these anonymized research participants but also their family members using available/public pedigrees. In response to this study, the NIH removed the age information from the project’s database. In another recent study, [33, 34], the authors reported that they can confirm whether a person participated in a genome-wide association study, by using information from the person’s DNA sample, “even if the study reported only summary statistics on hundreds or thousands of participants” [31]. In response, the NIH shifted to a controlled access mechanism. In fact, currently, most human genome projects use controlled-access mechanisms.

The personal information derived from genomic data (and EMR data) can be very damaging to the participants. It can be used against them to limit insurance coverage, to guide employment decisions, or to apply social stigma. In [35], the authors report on a case of genetic discrimination by a railroad company. The case occurred in 2002 when the company forced its employees to undergo a genetic test; employees who refused to participate in the test were threatened with disciplinary actions. The company was later forced (in an out-of-court settlement) to compensate 36 of its employees. That is hardly a consolation because if such genetic data was obtained from online sources or breached through illegal means, the company may have been able to get away with its discrimination practices.

Regulations

Guideline G2 depends on the availability of robust de-identification techniques, but as current techniques are outdated, and unable to deal with genetic and EMR data (as evident from the privacy breaches cited earlier), G2 cannot be adopted. The Vanderbilt genome project is the only project we are aware of that was ruled by Vanderbilt IRB to be a “non-human subject data” as it was deemed to be properly de-identified. However, given the potential impact of the project on the community, guidelines adhering to G1.b were enforced.

Guideline G1.a requires informed consent from participants. The problem with such requirement is that data collectors have to forecast all possible uses of the data and create a comprehensive consent detailing the benefits and risks related to all different data uses. Something that is not easily achievable. In fact, most biobanks collect consents in the form of opt in/opt out [19]. The issues/challenges in implementing proper informed consent will be discussed in depth later in this section.

Almost all existing biomedical data warehouses that house (non-aggregate) genetic data coupled with EMR data follow guideline G1.b. These warehouses lightly de-identify their data and regulate investigators’ access to the data through an IRB [18, 19, 40]. Only researchers with studies that involve less risk than benefit are allowed access to requested data and only after they pass a thorough identity check. However, IRB procedures are extensive and can obstruct timely research and discoveries [41–43]. Studies on platforms that rely on IRB for all data accesses reveal unsatisfied users. The application process is strenuous and approvals take a long time often delaying project initiation significantly [43, 44].

In Qatar, as an example, access to the biomedical data collected in Qatar is governed by the QSCH “guidelines, regulations and policies for research involving human subjects”, which adheres to guideline G1.b. A recently formed IRB will regulate all accesses to the research data and services by all research institutes within Qatar and outside.

With such massive mandates, a principal feature for IRBs is to have the capacity to foster timely research and discoveries. Data application processes and approvals should be smooth and should not delay project initiation significantly. Thus, the traditional “IRB-based” data sharing will produce unsatisfied users.

Methods under investigation

In what follows, we briefly describe recent efforts within each of the three technical categories.

Secure multiparty computation

Secure multiparty computations (SMCs) are an attractive approach that allows a researcher to run a function on data owned by multiple parties (each holding a fraction of the data to be analyzed). The calculation is carried out on the overall dataset without any party having to reveal any of their own raw data. Such scenario can be particularly useful for cross-institutional studies (or even cross-countries studies) particularly when no site has enough data to conduct the study in question (for example, studies on rare diseases).

Figure 3 illustrates the SMC concept. In the figure, a researcher wants to run a computation f over the private inputs of three remote databases (data1, data2, data3) while keeping these inputs private. The different parties are allowed to exchange messages with each other and with the researcher. However, such messages are encrypted so as to prevent the different parties from learning any private information through interaction.

SMC is gaining more popularity in the biomedical domain. SMCs are supported by robust mathematical proofs demonstrating their ability to securely protect privacy and thus proving their ability to support data sharing without fear of privacy abuse. In [66, 67], the authors designed a secure linear regression using homomorphic encryption for a multi-hospital quality improvement study. In [68], a secure genome-wide association study (GWAS) was designed using homomorphic encryption, and in [69], a GWAS protocol was designed using secret sharing. In [70], the authors use garbled circuits to perform metagenomics analysis.

In general, the protocols for secure computation have achieved outstanding results; it has been shown that any function (no matter how complex) can be computed securely. Efficiency however is the major drawback of these computations; they are much more complex than regular protocols (that do not provide any security) [71]. The complexity is driven by the extensive message passing between the involved parties as well as the cryptographic functions employed. Recently, the authors in [72] presented a fast and secure computation for linear regression over distributed data based on secure matrix multiplication. And, the authors in [73] designed another efficient secure multiparty linear regression protocol; their method was based on mathematical results in estimation theory. It remains to be seen whether these methods are generalizable to other estimators.