Building the Informatics Infrastructure for Comparative Effectiveness Research (CER): A Review of the Literature
Lopez, Marianne Hamilton MPA*; Holve, Erin PhD, MPH, MPP*; Sarkar, Indra Neil PhD, MLIS†; Segal, Courtney BA*
*AcademyHealth, Washington, DC
†Center for Clinical and Translational Science, University of Vermont, Burlington, VT
Supported by the Agency for Healthcare Research and Quality (AHRQ) through the American Recovery & Reinvestment Act of 2009, Grant U13 HS19564-01.
The authors declare no conflict of interest.
Reprints: Marianne Hamilton Lopez, MPA, AcademyHealth, 1150 17th St Suite 600, Washington, DC 20036. E-mail: email@example.com.
Background: Technological advances in clinical informatics have made large amounts of data accessible and potentially useful for research. As a result, a burgeoning literature addresses efforts to bridge the fields of health services research and biomedical informatics. The Electronic Data Methods Forum review examines peer-reviewed literature at the intersection of comparative effectiveness research and clinical informatics. The authors are specifically interested in characterizing this literature and identifying cross-cutting themes and gaps in the literature.
Methods: A 3-step systematic literature search was conducted, including a structured search of PubMed, manual reviews of articles from selected publication lists, and manual reviews of research activities based on prospective electronic clinical data. Two thousand four hundred thirty-five citations were identified as potentially relevant. Ultimately, a full-text review was performed for 147 peer-reviewed papers.
Results: One hundred thirty-two articles were selected for inclusion in the review. Of these, 88 articles are the focus of the discussion in this paper. Three types of articles were identified, including papers that: (1) provide historical context or frameworks for using clinical informatics for research, (2) describe platforms and projects, and (3) discuss issues, challenges, and applications of natural language processing. In addition, 2 cross-cutting themes emerged: the challenges of conducting research in the absence of standardized ontologies and data collection; and unique data governance concerns related to the transfer, storage, deidentification, and access to electronic clinical data. Finally, the authors identified several current gaps on important topics such as the use of clinical informatics for cohort identification, cloud computing, and single point access to research data.
Technological advances in clinical informatics have made large amounts of data accessible and potentially useful for research. As a result, a burgeoning literature addresses efforts to bridge the fields of health services research (HSR) and biomedical informatics. The goal of the Academy Health Electronic Data Methods (EDM) Forum is to facilitate learning and foster collaboration by working with 11 comparative effectiveness research (CER) projects [supported through 3 grant programs: Prospective Outcome Systems using Patient-specific Electronic data to Compare Tests and therapies (PROSPECT), Scalable Distributed Research Network (DRN) for CER, and the Enhanced Registry for Quality Improvement (QI) and CER] designed to build infrastructure and conduct CER with electronic clinical data (ECD). CER aims to determine what works best for whom and under what conditions1 and observational CER studies may leverage large amounts of data from numerous systems and sources. Clinical informatics platforms, models, and tools are being developed to support new infrastructure and studies across multiple sites and sources. As these efforts develop, it is important to understand the current state of the peer-reviewed literature at the intersection of CER and clinical informatics. The EDM Forum literature review aims to characterize this new body of literature on CER and clinical informatics, as well as identify cross-cutting themes and gaps in the literature.
The relatively new use of the term CER and the number of concepts related to CER can complicate efforts to develop an automated search for relevant articles. The National Library of Medicine has developed an initial strategy to identify CER in the peer-reviewed literature.2 According to PubMed search strategies applied in 2010, literature annotated with the Medical Subject Headings (MeSH) term for “comparative effectiveness research” as a topic generates extremely small results (n=375), whereas a search string classifying CER concepts tends to generate extremely large results (2 million citations or more).3 As a result, before this review, no existing PubMed4 search strategy has identified relevant articles on CER and clinical informatics (defined here as a specific subdiscipline of biomedical informatics that focuses on informatics in the clinical context as opposed to molecular biology or public health). On the basis of the input from librarians at the National Library of Medicine and the University of Vermont, we developed a multistep approach to search and identify relevant articles.
A 3-step, curated approach was used to identify relevant articles (the numbers of records retrieved per search are in parentheses), including:
Searching PubMed using MeSH terms (n=68). This effort focused on a set of search strings, MeSH terminology (including major headings “MH” and minor headings “mh”), and terms known to be associated with key projects, programs, and authors. In addition, using Boolean search techniques (AND, OR, NOT) enabled us to narrow the search. For example, one specific PubMed search used the following search string: ((“Informatics” [tiab] OR “Informatics” [MH] OR “Medical Informatics” [MH]) OR (“data mining” [MH] OR “information storage and retrieval” [mh])) AND (“Comparative Effectiveness” [tiab] OR “Comparative Effectiveness Research” [MH]). An additional keyword (KW) search was conducted for the “Learning Healthcare System,” generating 7 results.
Manual review of papers from select publication lists was then conducted, including articles referenced in: the PROSPECT, DRN, and Enhanced Registries study proposals (∼1500 citations); an annotated bibliography developed for the AcademyHealth project, Health IT for Actionable Knowledge (n=40)5; and a subset of papers presented at the 2010 American Medical Informatics Association Symposium (n=2).
The third step focused on reviewing articles identified in publication lists and/or Web sites from research activities related to the EDM Forum (ie, research based on prospective ECD). This list of projects was developed based on input and discussions with experts working on CER and informatics, including members of the EDM Forum Steering Committee. Projects include: caBIG (cancer Biomedical Informatics Grid),6 DARTNet,7 DEcIDE (Developing Evidence to Inform Decisions about Effectiveness),8 HMORN (HMO Research Network),9 iDASH (integrating data for analysis, anonymization, and sharing),10 i2b2 (Informatics for Integrating Biology and the Bedside),11 OMOP (Observational Medical Outcomes Partnership),12 PhysioMIMI (Multi-Modality, Multi-Resource Information Integration environment),13 REDCap (Research Electronic Data Capture),14 Sentinel Initiative and Mini-Sentinel,15 SHARP Program (Strategic Health IT Advanced Research Projects),16 TRIAD (OSU Clinical and Translational Science Awards),17 and VINCI (VA Informatics and Computing Infrastructure).18 Review of the available publication lists and project Web sites resulted in 818 potentially relevant articles. Although large datasets are an important source of information on health outcomes, the objective of the review is identifying activities focused on clinical informatics using ECD for research. As a result, this list of projects does not include research on large retrospective datasets that have been mined to answer effectiveness questions (eg, Medicare data files, surgical QI project data files, etc.).
Finally, to test our ability to identify key concepts that did not appear frequently in our searches, we conducted sensitivity tests of possible gaps by conducting individual PubMed searches, combining keyword and MeSH searches for specific key terms that did not appear to have been addressed.
Review and Coding
A total of 2435 citations were potentially relevant for the review. The initial article set (n=2435) was reduced (to ∼400) based on a manual review of titles and abstracts by a formally trained biomedical informatician (I.N.S.). The goal of this initial filtering process was to identify an unduplicated set of articles focused on the set of key concepts developed by the authors that reflect major topics at the intersection of clinical informatics and CER (Table 1).
To select the most relevant subset of articles, articles were excluded if they were not explicitly related to clinical informatics, or focused on genomic rather than clinical data, or clinical outcomes rather than the use of clinical informatics for research. The set of 400 citations then underwent another review of titles and abstracts using the exclusion criteria articulated above resulting in 147 articles. A full-text review was performed for 147 articles and the previously described exclusion criterion was used, resulting in 132 articles selected for discussion.
This final set of 132 articles was divided between 2 reviewers who abstracted and coded their assigned papers, using a standardized abstraction form designed specifically for the EDM Forum literature review. Because the goal of conducting CER with ECD brings together several multidisciplinary fields—specifically, bioinformatics and HSR—it was important to develop a list of salient concepts that are cross-cutting. The list of concepts was developed by a multidisciplinary team comprised of a biomedical informatician (I.N.S.) and HSR researcher (E.H.). The list was then reviewed by EDM Forum consultants, including a clinician and statistician; and members of the EDM Forum Steering Committee, many of whom are engaged in developing infrastructure and methods for conducting CER with ECD.
The list of key concepts was then used to code the review findings and characterize areas of focus, or gaps in the current literature. After the records were retrieved, each paper was coded with a primary area of focus to quantitatively assess the extent to which specific topics are currently addressed in the literature. Throughout the coding process, inconsistencies between the reviewers were deliberated and the list of concepts was refined. The final list of concepts is shown in Table 1. To validate the coding process, the reviewers randomly selected one third of the articles that were initially reviewed by the other reviewer, and conducted a second, independent review to compare categorization, resulting in a 77% rate of agreement and (Cohen’s) κ of 0.78, between the 2 reviewers.
One hundred thirty-two articles were selected for inclusion in the review (see Appendix for a list of selected references). Of these, 88 articles are the focus of the discussion in this paper.
Three types of articles were identified as major areas of focus for the current body of literature, including papers that: (1) provide historical context or frameworks for using clinical informatics for research, (2) describe platforms and projects, and (3) discuss issues, challenges, and applications of natural language processing (NLP). In addition, 2 cross-cutting themes emerged: the challenges of conducting research in the absence of standardized ontologies and data collection; and unique data governance concerns related to the transfer, storage, deidentification, and access to ECD. Finally, the authors identified current gaps on topics such as the use of clinical informatics for cohort identification, cloud computing, and single point access to research data.
Characterizing the Literature
Historical Context and Frameworks
Twenty-five papers (19%) provided context for the evolution of clinical informatics used to conduct CER. Taken as a whole, the papers present an overview of the history, challenges, and potential for conducting CER with ECD.
Three articles provide historical insights into early intersections between HSR and biomedical informatics, and the development of clinical informatics tools to conduct CER. The articles include foundational works on CER19 and papers defining keywords and scope relevant to using biomedical informatics for research.20,21
One emerging theme within this category is that multidisciplinary and multisite collaborations can enable new partnerships, which may in turn expand the availability of data, strengthen project sustainability, lead to research innovation, and minimize duplication of effort. Twelve of the articles address the opportunities and challenges of fostering and conducting multidisciplinary and multisite collaborations in HSR and biomedical informatics,22–35 with 2 articles specifically calling for cross-training between the fields.22,35
In one example, McCray et al’s23 review of several International Medical Informatics Association (IMIA) working group meetings illustrates the importance of multidisciplinary collaborations. The 1988 meeting included representation from linguistics, natural language analysis, medical decision-making, knowledge representation, and computer science, demonstrating the multidisciplinary nature of perspectives that influence the area of study. The authors’ summary of papers produced from the IMIA’s 1994 meeting reflects the value of convening researchers from diverse disciplines in the effort to “model[ing] medical knowledge” for a variety of uses in clinical care and research. The authors further note the collaborative nature of researchers in this arena, commenting on IMIA participants’ interest in discussing “the importance of sharing knowledge and tools and … continued and increased efforts to develop sharable research products.”
Yet, multidisciplinary and multisite collaborations can give rise to new challenges such as working with and obtaining approval from multiple IRBs.9 One perspective that emerged in the papers addressing multidisciplinary and multisite collaborations is that current funding and publishing practices offer few incentives to share data, which could negatively influence researchers’ readiness to engage in collaborative efforts.24,26 According to de Carvalho et al24 resistance to data sharing could negatively impact research:
In a system that emphasizes competition rather than collaboration among researchers, data sets resulting from multimillion investments from tax payers sit idle inside locked computers, only available to a small number of researchers despite their containing the seeds that would allow for the exploration of a vast number of important research questions that could change the healthcare landscape.
Platforms and Projects
Thirty papers (23%) describe the aims, content, functionality, and methods used by a variety of ongoing clinical informatics projects and platforms. Principally, the literature addressed the most well-established efforts, including: caBIG,36–39 DARTNet,40 HMORN,41–44 i2b2,31,45–47 OMOP,42 REDCap,48 Sentinel Initiative and Mini-Sentinel,42,49,50 and TRIAD.51 These papers provide an overview of various efforts that are underway using clinical informatics for research, many of which include information on the projects’ areas of focus; provide progress updates; or describe tools and platforms that have been developed or are in development.
NLP is used to extract relevant data from the free text embedded in electronic health records and text documents and is used in a variety of contexts, most commonly in HSR to conduct drug and vaccine surveillance, or effectiveness research. Thirty articles (23%) focus on NLP tools.
The literature on NLP focuses on tools for extracting relevant data from a variety of text sources and generating deidentified data applicable to the needs of research.52 Articles also describe the range of NLP techniques and frameworks being developed, used, modified, and evaluated.47,53–78
Ten papers discuss the i2b2 NLP data mining challenges, in which a variety of NLP techniques (eg, machine learning and rule-based approaches) were tested using the same set of data in an effort to develop new approaches for extracting information from clinical text. Three papers discuss the 2006 Smoking Challenge29,30,79 and 7 discuss the 2008 Obesity Challenge.31–36,80 In his overview of the Obesity Challenge, Uzuner80 describes that the challengers used NLP using 1237 discharge summaries annotated by 2 obesity experts. The annotations consisted of textual judgments (the classification of each disease based on explicit information in the documents) or intuitive judgments (the classification of each disease based on the expert’s intuition and judgment), and were evaluated using microaveraged and macroaveraged precision, recall, and F-measure (a statistical measure that considers both precision and recall). Rule-based approaches contributed to top performance within the textual category, whereas the machine learning approaches were more successful within the intuitive test.
The Need for Standardization
Conducting CER with ECD may involve data from different clinical informatics platforms and sources, and therefore, diverse systems with different ontologies81 and varying data collection practices must be anticipated. The need to standardize ontologies and data collection so that researchers can work together in multisite, multidisciplinary research collaborations is a prevalent theme.
Eight papers28,37,82–87 focus on the need for and/or application of standardized ontologies. Of these, Chute83 highlights the challenges of establishing common vocabularies because of the increasing number of naming mechanisms and resulting proliferation of medical terms in the field. The flexibility of the number of available clinical terminology systems coupled with the lack of standardized vocabulary for medical terms, has resulted in multiple names for single concepts. The author notes that this issue complicates researchers’ ability to share health information across sites.
The need to standardize data collection is an additional issue raised by the authors. Differences in ontologies, informatics platforms, and data entry practices contribute to the complexity of collecting and analyzing multisite electronic data for research. Three papers focus on the need to standardize data collection by applying common data elements.88–90 Seven papers27,40,49,91–94 highlight the challenges associated with collecting and analyzing data from multiple sites and informatics platforms, such as the differences in the data collected for clinical use versus research use,27 variances between the functionality of different EHRs,91 lack of standardization in how data are reported among multiple data sources,40,49,92,93 and difficulty in implementing standardization efforts after systems are operational.94
Data Governance and Access
CER based on ECD presents unique data governance concerns related to the transfer and storage,43,92,93,95–97 deidentification,98–102 and access of ECD.103–105 At present, the literature focuses on 2 primary issues: the need to ensure the security of transfer and storage of data; and the tension between preserving privacy (often by deidentifying research data) and enabling research data access.
In the literature to date, no consensus has emerged with respect to best practices for data security, especially regarding DRN or centralized data models.106 Proponents of DRNs argue that the model allows for local control because data never leave their home institution.43,95–97 In contrast, proponents of centralized data models assert that a centralized data warehouse can be more secure.92,93
Authors have also debated whether existing privacy regulations (ie, the Health Insurance Portability and Accountability Act, or HIPAA) provide sufficient protection to patients while balancing access to data for researchers. Two articles focus on the current standards for the protection and use of personal health information, arguing that research with deidentified data poses minimal risk.103,104 Five of the articles addressed the vulnerabilities of current deidentification efforts.98–102 Informed consent is also discussed as an issue impacting the availability of ECD for research. Goldstein105 discusses ways informed consent may be adapted in a changing climate of health care delivery, particularly with the ability for EHRs to strengthen security protocols and ensure patients are informed of various uses of their data.
Identification of Gaps
As discussed, the set of concepts initially developed by the authors reflect key topics at the intersection of clinical informatics and CER (Table 1). To the extent that the reviewers did not identify any relevant articles that aligned with the codes/concepts developed for the review (even after conducting specialized keyword searches), the authors assessed these concepts as being “gaps’ in the literature. No articles were identified as focusing on “cohort identification,” “cloud computing,” or “single point access” to research data. In some instances, each of these concepts were discussed as a challenge or issue in the context of papers on other topics, but were not the primary focus of the article.
The literature review demonstrates the degree to which the disciplines and fields focused on CER and clinical informatics are discussing approaches to advance the use of clinical informatics for research to improve patient outcomes. For example, the literature review illustrates the variety of approaches that use different data models or network strategies for CER. The range of efforts exemplifies the current focus on exploration and innovation in this arena. Similarly, differences of opinion regarding the utility of deidentifying data for research, and the associated privacy risks that may emerge, come to the fore. All of these cross-cutting themes reflect a nascent, but rich, discussion, and the breadth of perspectives in this growing community of scientists engaged in expanding the current paradigm of effectiveness research. The presence of notable gaps in the literature (eg, informatics strategies for cohort identification) underscores new opportunities for scholarship.
This first effort to characterize the literature relevant for CER and clinical informatics clearly demonstrates that there is no one discipline or field whose taxonomy can be used to readily access the relevant literature. For the near future, at least, the need to review important issues, tools, and techniques, and cross-reference key investigators is necessary to assemble the literature that is relevant to building the CER infrastructure. However, some limitations are inherent in this effort. For example, some topics identified as gaps in the literature may be because of limitations in our current search or coding processes. Another potential limitation is that the literature on clinical informatics and CER is still at its infancy and that some concepts of interest to CER investigators, while innovative and important, are not well established or may not have achieved peer-reviewed status. It is possible that some innovative approaches may be identified in the grey literature (research papers and reports that are not peer reviewed107). As a result, the EDM Forum is in the process of conducting a structured review of the grey literature to identify additional resources.
The EDM Forum has also made strides to develop and disseminate resources that facilitate ongoing review of the literature, including a set of PubMed search terms that provide a starting point for exploration; the EDM Forum’s abstraction form, which was created for this review; and an annotated bibliography of all the selected articles. A glossary of relevant terms has also been developed as part of www.edm-forum.org. Through these and related efforts we will continue to monitor the evolution of the literature on CER and clinical informatics.
Over the next 2 years, an influx of new research supported by the American Recovery and Reinvestment Act (ARRA) of 2009 and the Health Information Technology for Economic and Clinical Health (HITECH) Act is likely to result in new scholarship, particularly with respect to CER studies using ECD. Charting the progress of this emerging scientific endeavor promises unique and interesting challenges, and new opportunities for discovery that may only be achieved by bringing diverse literatures together. To this end, EDM Forum staff will be conducting an ongoing scan of the literature, in order to gather the latest published data on the intersection of clinical informatics and CER.
As part of this effort the authors are collaborating to develop an automated approach (ie, identification of keyword or MeSH descriptors that can be used with high reliability to identify relevant literature) that can facilitate our ability to identify relevant articles with greater precision. Of particular interest is developing methods to detect literature associated with gaps in the review.
Identifying literature that is relevant to clinical informatics and CER requires a clear conceptual framework of the particular issues that are most relevant to explore. The present review of CER and clinical informatics is unique in its effort to bring together literature from a number of domains, including technology, medicine, research, and policy.
Having characterized this initial literature, including multidisciplinary viewpoints and ongoing initiatives dedicated to developing an infrastructure for collecting and analyzing prospective ECD, the authors hope these materials will be useful to other investigators engaged in new approaches to conduct CER with ECD. Ideally, this review and the underlying approach will serve as the foundation for researchers to access relevant literature on clinical informatics for CER. This initial review is a first step toward aggregating and characterizing scholarship in CER and clinical informatics, as well as identifying themes and gaps that may be critical to address as part of an overarching strategy aimed at advancing science to improve patient outcomes.
The authors acknowledge the support of the Agency for Healthcare Research and Quality. The authors would also like to acknowledge Dr Sonia Nagda for her contribution to data collection and analysis.
Appendix. Summary Table of Articles on CER and Clinical Informatics Selected for Review and Discussion Cited Here...
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