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Methods for enhancing the reproducibility of biomedical research findings using electronic health records
© The Author(s) 2017
Received: 10 April 2017
Accepted: 28 August 2017
Published: 11 September 2017
The ability of external investigators to reproduce published scientific findings is critical for the evaluation and validation of biomedical research by the wider community. However, a substantial proportion of health research using electronic health records (EHR), data collected and generated during clinical care, is potentially not reproducible mainly due to the fact that the implementation details of most data preprocessing, cleaning, phenotyping and analysis approaches are not systematically made available or shared. With the complexity, volume and variety of electronic health record data sources made available for research steadily increasing, it is critical to ensure that scientific findings from EHR data are reproducible and replicable by researchers. Reporting guidelines, such as RECORD and STROBE, have set a solid foundation by recommending a series of items for researchers to include in their research outputs. Researchers however often lack the technical tools and methodological approaches to actuate such recommendations in an efficient and sustainable manner.
In this paper, we review and propose a series of methods and tools utilized in adjunct scientific disciplines that can be used to enhance the reproducibility of research using electronic health records and enable researchers to report analytical approaches in a transparent manner. Specifically, we discuss the adoption of scientific software engineering principles and best-practices such as test-driven development, source code revision control systems, literate programming and the standardization and re-use of common data management and analytical approaches.
The adoption of such approaches will enable scientists to systematically document and share EHR analytical workflows and increase the reproducibility of biomedical research using such complex data sources.
Electronic health records (EHR), data generated and captured during routine clinical care encounters across health care settings, have been recognized as an invaluable research resource [1, 2]. Increasingly, EHR are linked with genotypic data to enable precision medicine by examining how genetic variants influence susceptibility towards disease, validate drug targets, or modify drug response at a scale previous unobtainable. EHR research resources such as CALIBER , the Precision Medicine Cohort Initiative , the UK Biobank  and the eMERGE Network  enable researchers to investigate disease aetiology and prognosis [7–14] at unprecedented phenotypic depth and breadth by recreating the longitudinal patient pathway spanning genome to phenome and birth to death.
The replication of scientific findings using independent investigators, methods and data is the cornerstone of how published scientific claims are evaluated and validated by the wider scientific community [15–17]. Academic publications arguably have three main goals: a) to disseminate scientific findings, b) to persuade the community that the findings are robust and were achieved through rigorous scientific approaches and c) to provide a detailed description of the experimental approaches utilized. Peer-reviewed manuscripts should, in theory, describe the methods used by researchers in a sufficient level of detail as to enable other researchers to replicate the study.
A recent literature review  of research studies using national structured and linked UK EHR illustrated how a substantial proportion of studies potentially suffer from poor reproducibility: only 5.1% of studies published the entire set of controlled clinical terminology terms required to implement the EHR-derived phenotypes used. Similar patterns were discovered in a review of over 400 biomedical research studies with only a single study making a full protocol available . With the volume and breadth of scientific output using EHR data steadily increasing , this nonreproducibility could potentially hinder the pace of translation of research findings.
No common agreed and accepted definition of reproducibility currently exists across scientific disciplines. Semantically similarly concepts such as “replicability” and “duplication” are often used interchangeably . In this work, we define reproducibility as the the provision of sufficient methodological detail about a study so it could, in theory or in actuality, be exactly repeated by investigators. In the context of EHR research, this would involve the provision of a detailed (and ideally machine-readable) study protocol, information on the phenotyping algorithms used to defined study exposures, outcomes, covariates and populations and a detailed description of the analytical and statistical methods used along with details on the software and the programming code. This in turn, will enable independent investigators to apply the same methods on a similar dataset and attempt to obtain consistent results (a process often referred to as results replicability).
Electronic health record analytical challenges
A primary use-case of EHR data is to accurately extract phenotypic information (i.e. disease onset and progression), a process known as phenotyping, for use in observational and interventional research . Phenotyping however is a challenging and time-consuming process as raw EHR data require a significant amount of preprocessing before they can be transformed into research-ready data for statistical analyses . The context and purpose in which data get captured (e.g. clinical care, audit, billing, insurance claims), diagnostic granularity (e.g. post-coordination in SNOMED-CT vs. fixed-depth in ICD) and data quality vary across sources .
Electronic health records research reproducibility
REporting of studies Conducted using Observational Routinely collected Data (RECORD) recommendations on reporting details around EHR algorithms used to define the study populations, exposures and outcomes
RECORD guideline principle
The methods of study population selection (such as codes or algorithms used to identify subjects) should be listed in detail.
A complete list of codes and algorithms used to classify exposures, outcomes, confounders, and effect modifiers should be provided.
Describe in detail the selection of the persons included in the study (i.e., study population selection) including filtering based on data quality, data availability and linkage.
Authors should provide information on how to access any supplemental information such as the study protocol, raw data or programming code.
We argue that EHR research can greatly benefit from adopting practices used in adjunct scientific disciplines such as computer science or computational biology in order to reduce the potential irreproducability of research findings using such complex data sources. In this manuscript, we review and identify a series of methods, tools and approaches used in adjacent quantitative disciplines and make a series of recommendations on how they can be applied in the context of biomedical research studies using EHR. These can be used to potentially address the problem of irreproducibility by enabling researchers to capture, document and publish their analytical pipelines. Where applicable, we give examples of the described methods and approaches in R. Adopting best-practices from scientific software development can enable researchers to produce code that is well-documented, robustly tested and uses standardized programming conventions which in turn extend its maintainability. The primary audience of our work is the increasingly expanding cohort of health data scientists: researchers from a diverse set of scientific backgrounds (such as for example clinicians or statisticians) that have not been exposed to formal training in computer science or scientific software development but are increasingly required to create and use sophisticated tools to analyze the large and complex EHR datasets made available for research.
Methods and results
We searched published literature, gray literature and Internet resources for established approaches and methods used in computer science, biomedical informatics, bioinformatics, computational biology, biostatistics, and scientific software engineering. We evaluated and described the manner in which they can be used for facilitating reproducible research using EHR and address the core challenges associated with this process. Reproducibility has been identified as a key challenge and a core value of multiple adjunct scientific disciplines e.g. computer science [31–33] bioinformatics , microbiome research , biostatistics , neuroimaging  and computational biology .
Methods and approaches that can enable the reproducibility of biomedical research findings using electronic health records
Scientific software engineering principles
Create generic functions for common EHR data cleaning and preprocessing operations which can be shared with the community
Produce functions for defining study exposures, covariates and clinical outcomes across datasets which can be maintained across research groups and reused across many research studies
Create modules for logically grouping common EHR operations e.g. study population definitions or datasource manipulation to enable code maintainability
Create tests for individual functions and modules to ensure the robustness and correctness of results
Track changes in analytical code and phenotypt definitions using controlled clinical terminology terms by making use of a source code revision control system
Use formal software engineering best-practices to document workflows and data manipulation operations
Standardized analytical approaches
Build and distribute libraries for common EHR data manipulation or statistical analysis and include sufficient detail (e.g. command line arguments) for all tools used
Produce and annotate machine-readable EHR phenotyping algorithms that can be systematically curated and reused by the community
Use Digital Object Identifiers (DOIs) for transforming research artifacts into shareable citable resources and cross-reference from research output
Deposit research resources (e.g. algorithms, code) in open-access repositories or software scientific journals and cross-reference from research output
Virtual machines can potentially be used to encapsulate the data, operating system, analytical software and algorithms used to generate a manuscript and where applicable can be made available for others to reproduce the analytical pipeline.
Encapsulate both logic and programming code using literate programming approaches and tools which ensure logic and underlying processing code coexist
Scientific software engineering principles: modular and object oriented programming, test-driven development, unit testing, source code revision control;
Scalable analytical approaches: standardized analytical methods, standardized phenotyping algorithms and
Scientific software engineering
The nature and complexity of EHR data often requires a unique and diverse set of skills spanning medical statistics, computer science and informatics, data visualization, and clinical sciences. Given this diversity, it’s fair to assume that not all researchers processing and analysing EHR data have received formal training in scientific software development. For the majority of researchers, unconscious practices can creep into the developed code, which if never made publicly available, will never be discovered and yet underpin most published scientific claims. No researcher wants to be put into the position of retracting their manuscript from a journal or having to contact a scientific consortium to ask they repeat months of analyses due to an error discovered in their analytical code. While these issues are not unique in EHR research, they are amplified given its multidisciplinary nature.
There is a subtle but prevalent misconception that analytical code does not constitute software as it’s written for a statistical package (e.g. R  or Stata ) and not in a formal programming language (e.g. Python  or Java ). As a result, the majority of researchers inadvertently fail to acknowledge or adopt best-practice principles around scientific software engineering. This could not be further from the truth as, by definition, code written for transforming raw EHR into research-ready datasets and undertaking statistical analyses is both complex and sophisticated due to the inherent complexity and heterogeneity of the data. While not directly a technical solution, facilitating scientists to obtain up to date training in best practices through training initiatives such as Software Carpentry , can potentially enable them to produce better quality code.
There is no optimal manner in which scientific software can be developed for tackling a particular research question as this is intrinsically an extremely problem-dependent set of tasks. Adopting scientific software engineering best practices however can provide EHR researchers with the essential bedrock of producing, curating and sharing high-quality analytical code for re-use by the scientific community. In general, scientific code development can be divided into several different phases which are usually executed and evaluated in smaller, rapid iterations: planning, coding, testing, debugging, documentation and analysis. In each of these phases, a number of tools and methods exist that enable researchers to manage provenance, readability and usability of their code. We review several of the most critical ones: modular programming, test-driven development and source code revision control in sections below.
Modular and object oriented programming
Adopting a modular programming approach will allow EHR researchers to organize their code more efficiently and subsequently enable its documentation and re-use, both by them and other researchers. Modular programming is essentially a software design technique that emphasizes separating the functionality of a program into smaller, distinct, independent and interchangeable modules . This translates to splitting code (that is often produced as a single, large, monolithic file) into several smaller modules that contain similar operations or concepts and that in turn can be stored as independent source code files. These modules can contain anything from a collection of functions to process a particular set of data fields (e.g. convert laboratory test measurements from one measurement unit to another) or entire modules dealing with the intricacies of one particular data source (e.g. extract and rank the causes of hospitalization from administrative data).
Test-driven development and unit testing
Test-driven development (TDD) is a software development approach where automated tests are created prior to developing functional code . In addition to testing, TDD involves writing automated tests of a program’s individual units, a process defined as unit testing . A unit is the smallest logical component of a larger software application that can be tested. The majority of tools and languages used in EHR research have some mechanism to directly facilitate code testing. For example, in Stata code testing can be implemented using the testcase class in Mata while in SAS  unit testing is facilitated through the FUTS  or SASUnit  libraries. TDD can enable complex EHR pre-processing and analytical code to be adequately and thoroughly tested iteratively over the lifetime of a research project.
Source code revision control
Phenotyping algorithms defining disease cases and controls are often developed iteratively and refined when new data become available or changes in the underlying healthcare process model cause the data generation or capture process to change. In the CALIBER EHR research platform for example , phenotyping algorithms and their associated metadata are stored and versioned in a private version control system. This includes the actual SQL code for querying the raw data, the implementation details and logic of the algorithm, the diagnostic terms and their relative position used and any other relevant metadata (such as author, date of creation, date of validation) in a bespoke text-based format. This enables researchers to keep track of changes of definitions at the desired time granularity and facilitates the collaborative creation of algorithms. The metadata and implementation details are then made available through the CALIBER Data Portal  for other researchers to download and use.
Scalable analytical approaches
Standardized analytical methods
Scientific software is often at first developed behind closed doors and public release is only considered around or after the time of publication . The standardization of common analytical approaches and data transformation operations in EHR research will potentially enable the reproducibility of scientific findings and fuel a sustainable community around the use of EHR data for research. Adjunct scientific disciplines have adopted this principle through the creation of large software libraries that contain a variety of common analytical approaches [65, 66]. For example, Bioconductor  was established in 2001 as an open source software for performing bioinformatics operations based on R. It serves as a common software platform that enables the development and implementation of open and accessible tools. Bioconductor promotes high quality documentation, and enables standard computing and statistical practices to produce reproducible research. The documentation across sections of each project is clear, accurate and appropriate for users with varying backgrounds on the programming languages and analytic methods used. There is particular emphasis on programming conventions, guidance, and version control, all of which greatly benefit from being perfomed in a standardized manner.
Adopting similar approaches in EHR research can arguably allow researchers to use and re-use standardized data cleaning, manipulation and analysis approaches. The reproducibility pipeline may require a more explicit structure where specific analytic workflows are tied to complete processes illustrating the decision tree from data preparation to data analysis. The ability to reproduce biomedical research findings depends on the interconnection of stages such as detailing the data generation processes, phenotyping definitions and justifications, different levels of data access where applicable, specifics on study design (e.g. matching procedures or sensitivity analyses) and the statistical methods used. Building generic and re-usable software libraries for EHR data is challenging due to the complexity and heterogeneity across data sources. While some libraries for manipulating and analysing EHR data exist , these are narrowly focused on specific data sources are challenging to generalize across other sources, countries or healhcare systems. Building and curating software libraries following the best practices outlined in this manuscript and disseminating them with standard scientific output is recommended in order to grow and sustain a community of tools and methods that researchers can use. Examples such as Bioconductor can offer inspiration on how to build an active community around these libraries that will facilitate and accelerate their development, adoption and re-use by the community.
A key aspect of developing software tools for data processing is estimating the expected data growth and designing modules and tools accordingly to accommodate future increases in data. Given the steady increase in size and complexity of EHR data, workflow management systems used in bioinformatics such as Galaxy , Taverna , and Snakemake  can enable the development of scalable approaches and tools in EHR research. Workflow management systems enable researchers to break down larger monolithic tasks or experiments into a series of small, repeatable, well defined tasks, each with rigidly defined inputs, run-time parameters, and outputs. This allows researchers to identify which parts of the workflow are a bottleneck or in some cases which parts could benefit from pararellization to increase throughput. They also allow the integration of workload managers and complex queuing mechanisms that can also potentially lead to better management of resources and processing throughput . Pipelines can be built to obtain snapshots of the data, validate using predefined set of rules or for consistency (e.g. against controlled clinical terminologies) and then transform into research-ready datasets for statistical analysis. Such pipelines can then potentially be shared and distributed using container technologies such as Docker  or package managers like Conda . Docker is an open-source platform that uses Linux Containers (LXC) to completely encapsulate and make software applications portable. Docker containers require substantially less computational resources than virtual machine-based solutions and allow users to execute applications in a fully virtualized environment using any Linux compatible language (e.g. R, Python, Matlab , Octave ). Docker libraries can be exported, versioned and archived, thus ensuring that the programmatic environment will be identical across compatible platforms.
Limited backwards compatibility can often hinder the reproducibility of previous scientific findings. For example, newer versions of a statistical analysis tool might not directly support older versions of their proprietary data storage format or an analytical tool might be compiled using a library that is no longer available in newer versions of an operating system. These issues can potentially be mitigated through the use of virtualization . Virtual machines (e.g. Oracle VirtualBox , VMware ) are essentially containers that can encapsulate a snapshot of the OS, data and analytical pipelines in a single binary file. This can be done irrespective of the “host” operating system that is being used and these binary files are compatible across other operating systems. Other researchers can then use these binary files to replicate the analytical pipeline used for the reported analysis.
Standardized phenotyping algorithms
No widely accepted approach currently exists for storing the implementation and logic behind EHR phenotyping algorithms in a machine-readable and transportable format. The translation from algorithm logic to programming code is performed manually, and as a result, is prone to errors due to the complexity of the data and potential ambiguity of algorithms . In their work, Mo and colleagues describe the ideal characteristics of such a format such as the ability to support logical and temporal rules, relational algebra operations, integrate with external standardized terminologies and provide a mechanism for backwards-compatibility . The creation and adoption of computational representations of phenotyping algorithms will enable researchers to define and share EHR algorithms defining exposures, covariates and clinical outcomes and share them in a standardized manner. Furthermore, machine-readable representations of EHR phenotyping algorithms will enable their integration with analytical pipelines and will benefit from many of the approaches outlined in this manuscript such as version control, workflow systems and standardized analytical libraries [62, 81]. Finally, algorithm implementations can also be uploaded in open-access repositories  or software journals  where they could be assigned a unique Digital Object Identifier (DOI) and become citeable and cross-referenced in scientific output.
Publishing study data online or in secure repositories alongside the code to preprocess and analyse it may be possible in some biomedical research domains, but is typically not an option for EHR research given the strict information governance restrictions and legal frameworks researchers operate under. Additionally, EHR sources typically contain the entire patient history and all their interactions with health care settings but only a subset of the original data is used and it is therefore equally important to document and disseminate the process of data extraction as well as the post-processing and analysis.
Extracting the appropriate dataset for research involves specifying lists of relevant controlled clinical terminology terms, timing windows for study population and patient phenotypes, and eligibility criteria. The work of defining the extraction criteria is usually performed by data managers in conjunction with domain experts such as clinicians. The algorithm parameters and implementation details are subsequently converted to machine instructions (e.g. SQL), executed and resulting data are usually exported from a relational database. Although the rationale behind the extraction process and the machine readable code should bear equivalent information content, it is extremely difficult for a human reader to understand the underlying logic and assumptions by reading the code itself . It is also very challenging to fully reproduce the extraction using only the human readable instructions of the agreed protocol given the ambiguity of algorithms and the complexity of the data. Similar challenges exist for the preprocessing of EHR data, such as the definition of new covariates and clinical outcomes, as well as for the analysis and post-processing (such as plotting) of the extracted dataset and results.
A simple and time-honoured solution to this challenge is the provision of documentation alongside the code used for the extraction/preprocessing/analysis of EHR data. This approach however is often problematic as documentation can often be out-of-date with regards to the code, might be incomplete as it is often written after the analysis is finished and for large projects, linking the correct pieces of documentation to the specific locations in the code can be cumbersome. A potential approach to solving this challenge is literate programming. The concept of literate programming was introduced by Donald E Knuth  and is not limited to a specific analytical tool or programming language. Literate programming is the technique of writing out program logic in a human language with included (separated by a primitive markup) code snippets and macros. In practice, both the rational behind the data processing pipeline as well as the processing code itself are authored by the user using an appropriate integrated development environment (IDE). The resulting plain text document subsequently undergoes two processes, the first in which the code itself is executed (often referred to as tangling) and one in which the formatted documentation is produced (often referred to as weaving). The result is a well formatted rich text document, for example Hypertext Markup Language (HTML), which can often include the output of the executed code (e.g. plots, summary tables, analysis results) alongside the original code snippets and documentation (Fig. 5).
Examples of packages and libraries supporting literate programming and report generation in popular analytical/statistical software packages
Taking the literate programming paradigm ever further, compendia  are containers for distributing and disseminating the different elements that comprise a piece of computational research. These elements are also fundamental in the concept of literate programming, however in the case of compendia, the data are also contained in the output .
The challenge of reproducibility in science has been widely recognized and discussed . Scientists using EHR data for biomedical research face a number of significant challenges which are further amplified due to the complexity and heterogeneity of the data sources used and the cross-disciplinarity of the field. It is crucial for researchers to adopt best-practices across disciplines in order to enable the reproducibility of research findings using such data. In this manuscript we identify and present a set of principles, methods and tools from adjunct scientific disciplines that can be utilized to enable reproducible and transparent biomedical research using EHR. Enabling reproducible research using EHR is an ongoing process that will greatly benefit the scientific and wider community.
We would like to thank Václav Papež for his help in preparing the figures included in this manuscript.
This study was supported by the National Institute for Health Research (RP-PG-0407–10314), Wellcome Trust (086091/Z/08/Z), the Medical Research Council Prognosis Research Strategy Partnership (G0902393/99558) and the Farr Institute of Health Informatics Research, funded by The Medical Research Council (MR/K006584/1), in partnership with Arthritis Research UK, the British Heart Foundation, Cancer Research UK, the Economic and Social Research Council, the Engineering and Physical Sciences Research Council, the National Institute of Health Research, the National Institute for Social Care and Health Research (Welsh Assembly Government), the Chief Scientist Office (Scottish Government Health Directorates) and the Wellcome Trust. LS’s contribution was supported by the Wellcome Trust, grant number WT082178. This work was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001110), the UK Medical Research Council (FC001110), and the Wellcome Trust (FC001110).
Availability of data and materials
Final LATE Xmanuscript and R code examples will be uploaded to GitHub.
SD and LS designed and supervised the study; SD, AGI, MP, KD drafted the manuscript; All authors critically revised the manuscript and provided final approval; SD is guarantor. All authors read and approved the final manuscript.
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