Journal:HEnRY: A DZIF LIMS tool for the collection and documentation of biospecimens in multicentre studies

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Full article title HEnRY: A DZIF LIMS tool for the collection and documentation of biomaterials in multicentre studies
Journal BMC Bioinformatics
Author(s) Heinen, Stepahine; Schulze, Nick; Franke, Bernd; Klein, Florian; Lehmann, Clara; Vehreschild, Maria J.G.T.; Gloistein, Claas;
Stecher, Melanie; Vehreschild, Jörg J.
Author affiliation(s) University of Cologne, German Center for Infection Research (DZIF), University Hospital Cologne, Goethe University Frankfurt
Primary contact Email: Contact form
Year published 2020
Volume and issue 21
Article # 290
DOI 10.1186/s12859-020-03596-1
ISSN 1471-2105
Distribution license Creative Commons Attribution 4.0 International
Website https://bmcbioinformatics.biomedcentral.com/articles/10.1186/s12859-020-03596-1
Download https://bmcbioinformatics.biomedcentral.com/track/pdf/10.1186/s12859-020-03596-1 (PDF)

Abstract

Background: Well-characterized biological specimens (biospecimens) of high quality have great potential for the acceleration of and quality improvement in translational biomedical research. To improve accessibility of local specimen collections, efforts have been made to create central repositories (biobanks) and catalogues. Available technical solutions for creating professional local specimen catalogues and connecting them to central systems are cost intensive and/or technically complex to implement. Therefore, the HIV-focused Thematic Translational Unit (TTU) of the German Center for Infection Research (DZIF) developed a laboratory information management system (LIMS) called HIV Engaged Research Technology (HEnRY) for implementation into the HIV Translational Platform (TP-HIV) at the DZIF and other research networks.

Results: HEnRY is developed at the University Hospital of Cologne. It is an advanced LIMS designed to manage the processing and storage of specimens and aliquots of different specimen types. Features include:

  • monitoring stored specimens and associated information;
  • finding and storing data via query tools or Structured Query Language (SQL);
  • preparation of summary documents, including scannable search lists;
  • centralized management of the practical laboratory part of multicentre studies (e.g., import of drawing schemes and specimen processing steps);
  • preparation of aliquot shipments, including associated documents to be added to shipments;
  • unique and secure identification of aliquots through use of customizable Quick Response (QR) code labels directly from HEnRY; and
  • support of aliquot data transmission to central registries.

In summary, HEnRY offers all features necessary for biobanking LIMS software. In addition, the structure of HEnRY provides sufficient flexibility to allow the implementation in other research areas.

Conclusion: HEnRY is a free biobanking tool published under the MIT license. While it was developed to support HIV research in Germany, the feature set and language options allow much broader applications and make this a powerful free research tool.

Keywords: LIMS, biobanking, sample documentation, sample storage, sample management, sample processing, DZIF, TP HIV, multicentre studies, TI biobanking

Introduction

A biobank can be described as a repository in which biological specimens (biospecimens) and data of their respective donors are stored for use in biomedical research. It involves the systematic and standardized procurement, processing, annotation, storage, and ultimately distribution of biospecimens to researchers.[1] Biobanks enable cross-purpose research studies by rapidly providing sufficient and well-described specimens for experimental and translational experiments. Linkage of biospecimens with clinical data provides important insights to phenotypic disease information that is crucial in the current research environment.[2][3]

Today, the indexing, labelling, and storing of specimens in professional biobanks is usually managed by a laboratory information management system (LIMS), supporting the user with the administrative and coordinative tasks of specimen processing, as well as the collection and analysis of identified analytical data.[4][5] Ideally, a LIMS is also capable of exchanging data with other systems via software and hardware interfaces. Many LIMS on the market are also flexible, modular systems, which support the addition of functions according to the customer’s needs.

The features of a LIMS have changed over the years from a basic sample tracking tool to a resource planning system that manages multiple aspects of laboratory informatics. Common features of a LIMS include workflow management, record keeping, inventory management, data exchange interfaces, and reporting. A well-designed LIMS brings accuracy and accessibility to the flow of samples and laboratory data.[6][7][8][9] One particularly important aspect of a LIMS is the possibility for automation to increase processing speed while reducing workload, particularly for repetitive and predictable tasks.[8][10] By supporting the standardization of documentation and standard operating procedures (SOPs) for sample processing, a LIMS can also improve data and sample quality and reliability by minimizing documentation errors through automation.[1][11][12][13][14]

By using a LIMS with a database accessible to each employee, individually managed spreadsheets can be replaced. Representation of the collected and complex data is simplified by the use of database queries. Regular backups can ensure the safety and availability of laboratory data.

Most LIM systems on the market have high initial costs or license fees. Small or newly founded working groups usually lack the financial means to purchase such a system.[1] For the specific purpose of collecting and processing specimens of the HIV Translational Platform (TP-HIV) within the German Center for Infection Research (DZIF), we developed and here present the HIV Engaged Research Technology (HEnRY) LIMS. Due to excellent user feedback, we noticed that many of HEnRY’s features are required by a broad range of researchers. As such, we decided to release the tool under an open license and make it available to the community.

Implementation

Development

HEnRY is released under the MIT licence. The client has been under development by an agile structured team since 2014, using C#[15] with Windows Presentation Foundation (WPF)[16] and the .NET 4.5 framework.[17] An installer package for Windows platforms (Windows 7 up to Windows 10), as well as the source code are available upon request. The manual and short instructions for the program are available at http://www.tp-hiv.de/. The first production version of HEnRY was made available for participants of the TP-HIV on February 15th, 2017.

All data is stored in a Microsoft SQL database on Microsoft SQL Server 2012 or greater.[18] It is recommended to install the server and the databases in a protected network suitable for highly detailed and potentially stigmatizing patient data with considerable potential for misuse. For additional information, see Supplementary material 1, 2, and 3.

During the developmental process of HEnRY, a close collaboration with the laboratory staff, which represents the primary target group of the tool, and study coordinators was established. Both user groups gave continuous feedback to developed and requested features, which were tailored to their needs.

User feedback in the form of meetings and questionnaires was obtained at regular intervals. Requests and bugs were fixed in the context of monthly updates. Additionally, the lead developer accompanied the lab employees in their daily work routine with HEnRY to streamline the program to the actual workflow in the lab.

The HEnRY LIMS software has been in use at the University of Cologne since 2016, with currently seven active working groups.

Workflow

HEnRY specializes in the documentation of the storage and processing of blood specimens and aliquots in analytically working laboratories. It simplifies and accelerates laboratory work, increases the quality of documentation, and minimizes potential sources of errors. Information about studies, patients, specimens, aliquots, and processing steps is stored in a structured manner (see Fig. 1). This information can be exchanged via pseudonym export and import functions, which improves cooperation between different participants of the studies. Additional information can be found in Supplementary material 4, 5, and 6.


Fig1 Heinen BMCBioinfo2020 21.png

Figure 1. Snapshot of the biobanking view. The quick-view option of the box is opened.

Figure 2 shows a diagram of the workflow for multicenter studies and the use of HEnRY. An unlimited amount of users per study site is supported. Online access is available using the site's own Citrix access. A study supervisor or study coordinator can develop the study properties, drawing schemes, and processing steps and send the study design as an XML file[19] to other participating centers.


Fig2 Heinen BMCBioinfo2020 21.png

Figure 2. Scheme of HEnRY-usage and distribution of practical study data to participating centers in multicenter studies

In a setting of limited resources, HEnRY can be used as a standalone LIMS on one computer with, e.g., SQL Server Express editions for structured documentation of and label creation for biospecimens. Via the transfer of XML files, data for biospecimens can be shared with other laboratories, clinics, or project partners.

Study management

HEnRY offers the opportunity to manage any number of studies and respective workflows to support practical work in the laboratory. The name of the study, start and end date, and contact persons, as well as entire laboratory notebooks, down to descriptions of the chemicals used, can be added to a study (see Fig. 3). More importantly, a scheme for drawing blood, sampling, and aliquoting can be created for each study visit, allowing rapid processing of incoming specimens. Information about the storage location can also be stored in the study scheme (see Fig. 4). A study scheme also maintains all specimen-related information after processing. For example, if, after processing, 50 aliquots are derived from one specimen, all related information about creation date, aliquot type, amount, volume, container, study, and location are equally added and maintained for the 50 aliquots. By applying a study scheme, 50 aliquots with all properties are created in one click. Aliquots created via a study scheme are directly linked to the selected study. Different processing steps, including the chemicals used, are stored with the specimen, if the processing has previously been assigned to the study (see Fig. 4).


Fig3 Heinen BMCBioinfo2020 21.png

Figure 3. The processing letter in HEnRY used in the laboratory for the documentation of specimen processing

Fig4 Heinen BMCBioinfo2020 21.png

Figure 4. Snapshot of a drawing scheme in HEnRY

Multicentre studies

Study schemes with all the practical information (visits with respective sampling procedures, processing steps, chemicals to use, addresses, contact persons, and more) can be exported to XML files. A study coordinator can centrally design a study in HEnRY and distribute the XML file to all participating centers. For imported studies, all study specific fields are read-only and cannot be changed by the participating center. These fields are predefined by the protocol of the study (e.g., way of shipment for aliquots, addresses of participating centers, processing steps, and visit plans with respective sampling schemes). Only information specific to the local center, e.g., storage location, can be added to the imported drawing scheme.

This procedure was initially developed for the TopHIV study, which is centrally coordinated from working groups in Cologne and Hannover. The XML files for the study are available for download on the TP-HIV website.

Backend

HEnRY offers the opportunity to work with different databases. The user chooses the database to work with when starting the program. Specimens processed for different working groups or studies can be stored in separate databases to expedite analysis and restrict accessibility of the data.

Storage management and documentation

Patient records can be created directly in HEnRY or linked to another clinical database. One such interface is available for the HIV Observation System (HIObS) of Germany's Robert Koch Institute, located in Berlin.[20] For data security reasons, HEnRY allows only pseudonymous patient records. Any number of IDs used in different studies can be stored as aliases for one patient record.

HEnRY offers a large range of properties, which can be documented for each specimen or aliquot. Basic data such as specimen type, storage location, and creation date and time of the aliquot are mandatory. Identification of the person responsible for specimen processing is stored with the specimen or aliquot record. Container and storage location, including tower and rack (e.g., freezer, nitrogen tank, or breeding bench), are also stored (see Fig. 1). For frozen specimens, the amount of freezing cycles is notated to further define specimen quality.

Specimens and aliquots can be created one by one or by using the copy function for existing aliquots. For studies, large amounts of aliquots can be generated by applying study schemes (see above and Fig. 4).

Users can create any amount of storage systems with information on building, floor, room, and type of storage. Virtual boxes can be designed with a name and the box size, in which aliquots are placed. HEnRY will check for each position, if the slot is still free, to avoid doubled placements. A virtual look inside each box is possible (see Fig. 1), such that the user is at any time fully aware of the used space within the box and its content. Mass edit functions for almost all properties of the aliquot are available.

For the unique and secure identification of specimens and aliquots, HEnRY allows users to print their own customized labels. Labels can be created with or without QR code. The properties and their order printed on the label are user-customizable, with a direct preview in the interface (see Fig. 5). Labels can be stored as templates and are accessible to every user in the database. After printing a label, the printer icon in the biobanking view turns from green to red to limit double printing of aliquot labels (see Fig. 1).


Fig5 Heinen BMCBioinfo2020 21.png

Figure 5. Label designer for the creation of customize labels

Shipment module

In the shipment module, aliquots are prepared for shipment. Users can specify a shipment container and add aliquots for shipment to the box. It is possible to add aliquots to the virtual shipment box via scanning of the QR code or a search function using the patient ID. It is also possible to run full SQL statements from the interface for more complex searches. In cases where the storage box is identical to the shipment box, the whole box and the contained aliquots can be selected by choosing the box. Reports concerning the content of a package can be created and printed. The reports available in the shipment module (in the XPS or CSV formats) contain a visual layout of the box and a list of aliquots with their properties. The study supervisor can preselect the properties of the aliquots saved in the CSV file. A customization of the range of properties and their format is possible. Additionally, a letter to address the receiver of the shipment is able to be generated.

Important information such as the reason for and method of shipment, as well as the delivery address, can be added by the study assigned to the aliquots.

User right administration

HEnRY features user management with different levels of access. The study supervisor has the right to manage and add studies within HEnRY. The study supervisor can monitor the completeness and the correctness of information contained in the HEnRY database. This guarantees ongoing and steady control of processing quality. After a study ends, the study supervisor has the option to anonymize patient data in-line with patient privacy rights. Laboratory staff is allowed to edit the specimen processing protocol.

If HEnRY is linked to a clinical database, clinical and personal data of patients can be viewed by users with the “physician” right. Otherwise, only pseudonymous data is shown. Users in the “IT” user group can administrate the SQL connection, manage HEnRY users, and adjust print settings.

Export of aliquot data

Only pseudonymous data can be exported. Data of specimens and aliquots can be exported into XML files, e.g., in order to merge data from one specific center with a central biobank. In our local use-case, merged data is delivered monthly to the DZIF's LIMS.[21]

Queries and reports

HEnRY offers a variety of search functions. Aliquots can be selected by study, visit, storage, or site. A graphical user interface offers a virtual view of a selected box, including the amount and placement of aliquots within the box. The monitoring status of all aliquots can be assessed and printed. All lists can be exported as XPS or CSV files.

Data can also be selected via an SQL query interface and printed as scannable search lists with QR codes for each aliquot. By use of this tool, researchers can perform complex and customized searches covering all data contained in the database.

HEnRY parser

To connect external data sources, a separate module is available for HEnRY, offering extract, transform, and load (ETL) processes for different source formats (e.g., MDB, CSV, HL7). The parser is not part of the primary program package.

Data protection and security

In view of the increasing requirements towards data protection standards in Europe, and especially Germany, data privacy officers and clinical IT departments are sometimes reluctant to allow the use of LIMS tools based on cloud services and web interfaces, especially in the context of potentially stigmatizing diseases such as HIV. HEnRY can run with a locally administrated Microsoft SQL database and offers hierarchical user rights on database and frontend levels. The storage of data, backup plans, and access to the data are fully controlled by the local IT department of the hospital. Therefore, this tool can be seamlessly integrated into high-security environments.

For large working groups, HEnRY works with a central Microsoft SQL Server and multiple clients. If access from outside the clinical network is necessary, HEnRY can be used via secure remote access solutions and has been successfully integrated into a Citrix Workspace environment.

Results

In 2012, a survey was performed among HIV specialists and cohort researchers in the DZIF to identify the state of affairs and any pressing needs in IT development across sites. Based on the survey results, a need for a harmonized collection and reporting of biospecimens was recognized. While some sites already had highly developed biobanks with professional software and storage solutions, most partners used legacy software products or standard spreadsheet software packages to maintain biospecimen and related data collections. Based on the obvious demand for a cheap and efficient solution, the decision was made to develop a common tool for specimen collection and exchange. An initial list of desirable features was made, and development of HEnRY started in 2014.

The lead developer of HEnRY went to on-site half-day visits to various users to directly understand the current and desired workflow and better address concerns and queries. Two working groups took the role of key users, who received early designs for commenting, and took part in workshops between users and developers to identify core workflow parameters. Many key features of HEnRY such as study schemes have been developed in direct collaboration with the laboratory staff of the key user groups. During 11 meetings with both key user groups between 2015 and 2018, features were improved, performance optimized, and bugs removed. The current version is 2.2.

After successfully deploying production versions of HEnRY for the key user groups in 2015 and 2016, HEnRY was requested by several other groups at UHC and DZIF. Table 1 shows an overview of the collected data for specimens, aliquots, and studies in HEnRY databases of different working groups at UHC. Currently, 2,574 patients, 7,953 specimens, and 68,519 aliquots are managed in HEnRY at the UHC for 23 ongoing studies.

Table 1. Overview over the data contained in different working groups using HEnRY; data from 10 January 2020
Laboratory Research field Installation date Patients Primary specimens Aliquots Studies
Group A Virology October 2015 1,086 2,459 34,229 10
Group B Infectiology March 2016 291 1,203 20,499 1
Group C Infectiology May 2017 367 2,402 7,984 4
Group D Infectiology August 2018 17 287 1,007 1
Group E Dermatology November 2018 20 40 400 1
Group F Nephrology January 2019 658 1,402 3,662 6
Group G Virology September 2019 122 122 649 2
Group H Tumorgentics with cell lines December 2019 3 18 15 0 (LIMS)
Group I Oncology December 2019 10 20 74 4

To improve the accessibility of biospecimens within the scientific community, specimens obtained with broad patient consent for certain biobanking studies are automatically reported to the central biospecimen registry (zentrale Bioprobenregister ZBR) of the TI Biobanking.[21] From there, specimens can be selectively requested for research. As of now, 279 patient data sets were reported, along with 19,034 data sets for aliquots.

Discussion

We performed a comprehensive comparison of HEnRY with other LIMS based on information available on the respective product websites.[22][23][24][25][26][27] Since many LIMS concentrate on the documentation of laboratory work and storage, only some advertise study workflow support[22][24][28][29][30] and laboratory process management[23] functionality for those conducting multisite studies. The possibility of creating customized labels was advertised by only a few LIMS vendors.[22][23][27] The integration of shareable SQL queries for patient and specimen identification was only identified in one other LIMS, and that was linked to a specific licence.[22] As a free system, HEnRY is well suited for: (i) use in low-resource environments, where HEnRY can be implemented without extensive IT experience on most Windows PCs with a free version of Microsoft SQL Server; and (ii) multiple decentralized instances within one network, which is an asset, especially for European research sites regulated under the European Union's General Data Protection Regulation (GDPR).[31][32][33][34][35][36][37][38][39]

Our software is not without limitations. One shortcoming of HEnRY compared to commercial tools is the current lack of support for robotics and rack scanners.[26] However, since HEnRY is developed for scientific research groups, such features have not yet been requested by existing key users.[40] Another limitation of HEnRY is the C# code base, binding the product to the Microsoft software environment, which can be associated with higher costs for license fees for operating system and database servers. However, not only may newly founded research groups lack IT support to implement complex Linux and/or web-based solutions, but also funding for commercial systems and extensive external support. Given sufficient administrative rights, HEnRY can be set up with low to medium IT experience on a local Windows system and later be up-scaled for higher user numbers, connected systems, remote access, and ETL processes. Finally, HEnRY does not yet fulfil all desirable standards of semantic and syntactic interoperability. Still, with a comprehensive XML interface for specimen data and workflows, package lists, and numerous ETL options for data import, interoperability in most environments can be achieved with moderate additional workload.

Conclusion

With HEnRY, we provide a free, versatile open-source LIMS tool published under the MIT license and designed for coordination of local biobanks, as well as central management of multicenter studies.

The individual features of HEnRY—e.g., connecting specimen and patient data, visualizing storage containers, tracking specimens, and managing biorepositories—have already been offered through other biobanking systems in the past.[22][23][24][25][26][27] We are, however, unaware of any LIMS besides HEnRY that would combine all of these features in the context of an open-source solution.

In conclusion, to our knowledge, HEnRY is the most comprehensive and versatile biobanking LIMS among the group of free and open-source systems. HEnRY allows safe and rapid implementation of a local and/or central LIMS system, thus offering immense potential for emerging research groups, especially in the setting of limited resources and/or complex multicenter studies.

Outlook

We envisage an extension of the list of annotatable specimen and aliquot types, organisms, and associated diseases, as well as machines used for specimen processing, in order to improve the depictable level of documentation precision in non-HIV scientific research. Given the growing importance of system connectivity features and data exchange, standard metadata and support for current health data exchange protocols such as the Health Level 7 FHIR Specification[41] and BBMRI-ERIC's MIABIS Community Standard[42] are expected to be added. With a sufficiently large user group, we intend to transfer the copyright to a non-profit foundation for further development and maintenance of HEnRY.

Supplementary material

Supplementary material 1: Class Diagram HEnRY (.png)

Supplementary material 2: Database scheme for specimens and aliquots (.png)

Supplementary material 3: Data flow 1 (.pdf)

Supplementary material 4: Data flow 2 (.pdf)

Supplementary material 5: Work flow (.pdf)

Supplementary material 6: Use case with user rights (.pdf)

Availability and requirements

Project name: HEnRY biobanking tool

Project home page: http://www.tp-hiv.de/

Operating system(s): Windows

Programming language: WPF, C#

Other requirements: .Net 4.5, Microsoft SQL, Microsoft SQL Server 2012 or greater

License: MIT

Any restrictions to use by non-academics: non-commercial usage

Acknowledgements

We would like to thank the RKI for the good and friendly collaboration.

A special acknowledgement belongs to Carola Ruping and Maike Schlotz from the working group of Prof. F. Klein, Ute Sandaradura de Silva from the working group of PD. C. Lehmann, and Sandra Winter from the working group of P.D. J. Rybniker for their collaboration and their constructive feedback. Especially the opportunity to observe the use of HEnRY in the daily laboratory work represented a valuable source and input to optimize the development of HEnRY. We also like the thank Dr. A. Illerhausen and Dr. Veronica di Cristanziano for using HEnRY.

We thank Dr. I. Suarez for using HEnRY for the specimen documentation of a tuberculosis study.

Contributions

SH carried out the major part of the program design, project coordination and did the major part of the programming. NS participated in programming and testing. BF participated in the design of the database and programming of the parser. JV consulted and supervised the project. All authors read and approved the final manuscript.

KF, CL, RJ, VM, GC, and the members of their working groups gave ongoing feedback from the laboratory or/and tested the software. HS joined the working groups to experience HEnRY in the practical daily laboratory working processes. SM tested the software and gave feedback as study coordinator.

Funding

Funding (FKZ: 8018504902): April 1, 2016 - March 31, 2017 = € 22,433.70.

Funding increase (FKZ: 8018504902): July 1, 2016 - December 31, 2016 = € 17,183.93.

This means 90% from the Federal Ministry of Education and Research BMBF (via DZIF) and 10% from the Ministry of Innovation, Science and Research of the State of North Rhine-Westphalia. The funding had been approved for software development.

Funding for the collection, interpretation and analysis of data is not applicable.

Ethics approval and consent to participate

For the HEnRY Software an ethical approval has not been necessary, since the software itself does not contain patient or medical data.

Ethical approvals are necessary for studies in which HEnRY is used.

The TopHIV study is a project within the TP-HIV by the German Centre for Infection Research (DZIF) (NCT02149004). Patients who participate in the TopHIV study additionally sign a patient consent, which can be viewed on tp-hiv.de. See also: https://www.clinicaltrials.gov/ct2/show/NCT02149004

Competing interests

The authors declare that they have no competing interests.

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Notes

This presentation is faithful to the original, with only a few minor changes to presentation, grammar, and spelling. In some cases important information was missing from the references, and that information was added. Several URLs in the original no longer work; working URLs presumed to be the intended source were substituted for this version. Several superfluous citations to .NET and other technologies were either turned into external links or omitted for this version.

The original paper—likely translated from German—unfortunately refers to biological specimens as "biomaterials," which adds significant confusion to the average reader. To avoid confusion with the concept of actual biomaterials used in medical device and clinical diagnostic design and manufacturing, all instances of "biomaterial," including in the title for this version, were replaced with "biological specimen" or "biospecimen." Mentions of "sample" were in most cases replaced with "specimen," unless sample management capabilities of a generic LIMS were being referenced, or the actual process of sampling was mentioned.