Case Report Forms (CRFs) are a common data collection mechanism in clinical studies and are sometimes the original recording of study data. CRF completion is one of the earliest opportunities to assure accurate and complete data and to decrease downstream work associated with identification and resolution of data discrepancies. This chapter covers development, maintenance, and implementation of instructions for CRF completion, also called CRF Completion Guidelines (CCGs). Recommendations in this chapter are based on the International Council for Harmonisation (ICH) E6 addendum,
After reading this chapter, the reader should understand
The purpose of a regulatory basis for CRF completion guidelines
The contents and organization of CRF completion guidelines
Creation and maintenance of CRF completion guidelines
Training clinical investigational sites and CRAs on CCGs
Data collection forms, commonly called Case Report Forms (CRFs) in clinical studies, have been used since the earliest studies. The main goal of paper and electronic CRFs alike is the consistent and accurate collection and recording of data. CRF Completion Guidelines (CCGs) support this by detailing the activities involved in CRF completion, correction, signing, and data handling.
Lack of adequate instruction on data collection forms has been cited as a common problem in clinical studies.
Form completion instructions may include diagnostic criteria, definitions of terms used on the form, specifications of time points for observations, measurement methods and equipment, units, precision, and significant figures for continuous data elements, as well as guidelines for handling variability, uncertainty, inconsistency, and error found in source documents or encountered in measurement. When study conduct necessitates decisions such as coding, calculations, or classification of data by sites during data collection, these are specified in CCGs. As such, the CCGs establish traceability for data origination and collection activities.
This chapter describes creation and maintenance of CCGs, their format, content, and implementation toward the precise, accurate, and consistent capture of clinical study data. CRF completion guidelines may cover observation and measurement procedures, important relationships between data elements, instructions as to where data values are likely to be found in the medical record, and which data values to choose as well as how to record the data on collection forms.
CCGs specify operations performed on data during observation, measurement, abstraction from source documents, and form completion. Regulation and guidance also address these processes. The ICH E6(R2) Good Clinical Practice: Integrated Addendum contains several passages particularly relevant to CCGs.
“Sponsors should focus on trial activities essential to ensuring human subject protection and the reliability of trial results” and that
“The methods used to assure and control the quality of the trial should be proportionate to the risks inherent in the trial and the importance of the information collected.” Identification of “processes and data that are critical to ensure human subject protection and the reliability of trial results” is specifically stated, as is risk management focused on the processes and data deemed critical.
The Medicines and Healthcare products Regulatory Agency (MHRA) GXP Data Integrity Guidance and Definitions addresses principles of data integrity, establishing data criticality and inherent risk, designing systems and processes to assure data integrity, and also covers the following topics particularly relevant to CCGs:
Similar to ICH E6(R2), MHRA
The FDA guidance, Use of Electronic Health Record Data in Clinical Investigations, emphasizes that data sources should be documented and that source data and documents be retained in compliance with 21 CFR 312.62(c) and 812.140(d).
Similarly, the FDA’s guidance on electronic source data used in clinical investigations recommends that all data sources at each site be identified.
As such, we state minimum standards for the creation, maintenance, and implementation of CCGs in
Minimum Standards.
1 | CCGs specify procedures for observation, measurement, abstraction from source documents, and form completion. As such, they support the evaluation of study conduct and the quality of the data produced. CCGs should exist for every study. | |
2 | CCGs should specify procedures for assuring that data are Attributable, Legible, Contemporaneous, Original, and Accurate, Complete, Consistent, Enduring, and Available (ALCOA +) and Traceable. | |
3 | CCGs should exist within a quality management system focused on “ensuring human subject protection and the reliability of trial results” |
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4 | CCGs should be considered essential documents and managed as such. A standard operating procedure(s) covering the process by which CCGs or equivalent documentation are created, versioned, reviewed, approved, updated, and distributed should exist. | |
5 | CCGs are developed for the use of study personnel, usually site coordinators and monitors. | |
6 | CCGs should be concise, current, easy to understand, and available to those performing relevant study operations. | |
7 | Training on CCGs should be provided and documented for individuals with responsibility in observation, measurement, abstraction, and form completion processes. Such training should occur prior to study enrollment and should be revisited upon significant updates to CCGs. | |
8 | The quality management system in which the CCGs exist should provide for ongoing oversight and control of observation, measurement, abstraction, and form completion processes. | |
Best practices were identified by both the review and the writing group and are presented in
Best Practices.
Develop guidelines in collaboration with the same roles that designed the CRF. These include protocol authors, form designers, investigators, practicing physicians, statisticians, site and medical monitors, site-based study coordinators, those familiar with the study database system, data entry, and data processing. |
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Develop standard CCGs that accompany standard CRF modules that can be used across studies if external standards do not exist. |
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Where external standards exist for data element definition and collection instructions, use them if appropriate for the study. |
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Allow sufficient time for development and testing of forms and instructions. |
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CRF and CCGs cannot be finalized prior to finalization of protocol. |
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Design CRFs and associated CCGs simultaneously with protocol development. |
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Hold dedicated meetings for timelier review and finalization of the CCGs. |
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Ensure that the format and content of the CRF/eCRF and the CCGs that provide instructions the form completer are “self-contained;” i.e., with all needed instruction or context available on the CRF/eCRF. |
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Ensure that standard CRF modules are accompanied by associated CCGs and QA guidelines. |
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Include detailed instructions on proper CRF completion where needed; i.e., where proper completion is not obvious based on form context. |
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Do not ask leading questions or otherwise suggest answers to users completing the forms. |
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Ensure forms are clear, provide necessary instructions, and are easy for the investigator to complete. |
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Place instructions and graphics that guide form flow on the form so that it is clear where to stop procedures or form completion or where to skip to. |
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Clearly state on the form the circumstances under which an item should be skipped. |
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Provide instructions for recording missing data. For example, include instructions to leave an item blank or to provide more information such as “asked but not answered” or “not done.” [VI] | ||
Provide necessary definitions and instructions on the form, next to the item to which they apply. |
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Accommodate linguistic and cultural differences within the CCGs. |
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Include on the form all of the information needed to understand an item on a form. In addition to the prompt or question, it may be necessary to include a basis of comparison; e.g., over the last 24 hours, since the last visit, the assessment, time points and units of measure, precision and number of significant figures, measurement method. |
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Provide explicit guidance as to order of day and month and to clarify noon versus midnight on a twelve-hour clock. |
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Define important diagnoses with clear criteria. |
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If calculations are required to inform immediate site action and these cannot be automated instructions (e.g., a worksheet) on how to complete and check the calculations should be provided. |
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Clearly state within the form’s instruction the role of the individual(s) completing the form, e.g., physician, research staff, patient, or proxy. [VI] | ||
Use innovative technology when possible to improve the usability, accessibility, and availability of CCGs. For example, CCGs may be included in electronic help and be available on the screen. [VI] | ||
Provide training on CRF completion. |
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Use appropriate techniques such as analysis or data trends or review of monitoring reports to identify undesirable events and trends in data collection and recording to prompt improvement of CCGs. [VI] | ||
Re-educate site personnel as needed and revise CRF completion guidelines as necessary, particularly for long-term studies or if a protocol amendment affects the completion of the CRF. [VI] | ||
Provide data management, biostatistics, medical writing, and other clinical research team members with finalized CRF completion guidelines so these groups are aware of how data are collected and recorded. [VI] | ||
Establish metrics through which site performance in CRF completion will be assessed at a frequency commensurate with the study length. [VI] | ||
CCGs should be tested by study staff. |
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Question or the wording of prompts can influence the answer. All questions and wording of prompts should be reviewed for its potential to bias data collection or recording. |
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GCDMP Evidence grading criteria.
Evidence Level | Criteria |
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I | Large controlled experiments, meta, or pooled analysis of controlled experiments, regulation or regulatory guidance |
II | Small controlled experiments with unclear results |
III | Reviews or synthesis of the empirical literature |
IV | Observational studies with a comparison group |
V | Observational studies including demonstration projects and case studies with no control |
VI | Consensus of the writing group including GCDMP Executive Committee and public comment process |
VII | Opinion papers |
Because the CCGs document the process by which data are collected or recorded, they should be considered essential documents.
Increasingly, standards exist for data elements used in clinical studies and instructions for observing, measuring, or otherwise obtaining the corresponding data. Examples of these include the Brighton Collaboration guidelines for collection, analysis, and presentation of vaccine safety data
CCGs accomplish their goal of increasing consistency in data collection and recording by serving as a job aid to those collecting and recording data. As such, they should be written in plain and precise language and simple sentences.
While some recommend starting CRF design after a finalized protocol, ostensibly to reduce rework in form design as the protocol evolves toward finalization, others recommend simultaneous work on the protocol and CRF.
The author initiates the creation of the CRF completion guidelines document during or following CRF design. The person drafting the CCGs must be familiar with the protocol and corresponding CRF.
A data manager or anyone with the appropriate knowledge of the protocol and relevant data can serve as the author of CCGs. The CCGs are developed in close collaboration with the following members of the study team.
a protocol author, clinical scientist, or a clinical study physician familiar with the study objectives and therapeutic area
a biostatistician with knowledge of the statistical analysis plan for the study
a drug safety physician or the study medical monitor
team members responsible for site initiation and study monitoring or others having regular contact with site staff
those familiar with the study database system, data entry, and data processing
The study team members outlined in the previous section should review the draft CCGs. [VI] The review should focus on ensuring that the CCGs are complete, correspond to the protocol, and provide adequate specification to the investigators, site staff, and monitors who will be using the guidelines. [VI]
The CCGs impact data collection and should be managed as a controlled document.
The CCGs should be revised when any of the following occur: [VI]
a protocol amendment is issued that has an impact on CCGs,
changes to the database affect the eCRF completion guidelines
when a trend in queries is identified that show that the CCGs are not adequately guiding the site staff on CRF completion
an error in the CCGs has been identified that has an impact on the CRF completion
The changes made to the CCGs should be highlighted or summarized, e.g., in a revision history section in the new version, in order to help study personnel to identify the changes. [VI]
Enough time must be allocated to create, review, and approve the CCGs. [V] Approved CCGs should be made available to the site staff before they enroll any subjects in the study.
Where CCGs include medical record abstraction guidelines, they should be reviewed and tested by several sites prior to use.
If CCGs are not electronically available through the EDC system and a separate document is being used for the CCGs, the distributed copy should be made available to personnel involved in data collection and recording.
Sites should be trained on form completion prior to enrolling subjects in a study.
CCGs can have multiple formats depending on the needs of the study. The author of the CCGs determines the best medium to use. For studies utilizing paper, CRFs the CCGs are often provided as guidance within the CRF booklet.
As best practice, it is useful for organizations to create a CCG template that can be used across studies.
There are several options for placement of form instructions including: on adjoining facing pages, on the top of the page, throughout the page, and on the front page for the visit. Placing instructions on the back of the page to which they refer is not recommended because they cannot be viewed while completing the form.
Electronic forms as described in the EDC Chapters provide additional options for making instructional information available during form completion. Such options include mouse-over or click-to-open help on a per question basis. Further, as described in the EDC chapters, electronic forms provide the ability to enforce data element structure such as “Select only one” or code lists for discrete data elements and significant figures and precision for continuous measures. Workflow such as skip patterns, stops, and availability of conditional and additional forms, may also be enforced. Such workflow automation is a form of external representation in that instructions are embedded in the functionality of the system and do not depend on a form completer reading or attending to them.
Regardless of the format, each question for which instructions exist should indicate where instructions are to be found.
The CCGs should be based on the protocol and case report forms. [V] CCGs should provide unambiguous instructions on CRF completion for, “all practical scenarios” that a one might encounter such as multiple data values, repeated assessments, data collected outside the study schedule, data corrections, and data resulting from unanticipated events.
Sections 2.10 and 4.9 of E6(R2) indicate that the CCGs or other study documentation should identify the expected source for all study data.
The CCGs should include general guidelines as to the expected turnaround time for CRF completion, e.g., according to E6(R2) section 4.9.0, general timeline expectations as well as expectations for contemporaneous data recording
Clarifying rounding rules and abbreviations and how to properly document visits or assessments that were not performed should be clearly detailed. The CCGs should provide field definitions in cases where the field needs more guidance to reduce ambiguity.
Instructions should also be used to call out linked data; for example, where an adverse event indicates a drug was given, prompting the form completer to enter the drug on the concomitant medication page.
For paper studies, it is important to outline how to complete the forms ensuring legible entry utilizing indelible ink. How to properly document any required updates by ensuring the original text is still visible, including adding the initials and date of the person completing the update, should be clearly detailed in CCGs, per ICH E6(R2), section 4.9.3 and Bellary.
CCGs written for site investigators and research staff differ from those needed by patients. Where forms designed for one type of form completer will be utilized with a different type of form completer, the language and type of instructions provided in the CCGs should be re-evaluated.
For international studies or studies where participants from different cultures or who speak different languages are expected, the CCGs may need to provide support to sites in accounting for those differences.
For EDC studies, a section of CCGs should be devoted to clarifying the field/eCRF dynamics that have been included in the study design. For example, specifying which eCRFs are present once a subject is created in EDC and what entry is required in order for additional forms or visit folders to populate. This will help ensure that site personnel understand how to complete all of the expected entry. Outlining which eCRFs are required based on a subject status should also be included in this section. For example, the complete casebook may be expected for a subject who completed the study per protocol; however, only a selected amount of screening eCRFs may be required for collection on a subject who is a screen failure.
Where the medical record is the source of the information, the process of reviewing the medical record and identifying the needed data is called Medical Record Abstraction (MRA) or chart review. Form completion instructions should specify where in the chart data needed for the CRF is to be found.
Medical evidence was categorized by Feinstein et al. as a description, a designation, or an interpretation.
Missing or otherwise imprecise data in descriptive information occurs when the medical record does not contain documentation of the desired observations or test results. In this case, the CCGs can only document applicable “null flavors” and when to use each. (See the instructions for handling missing data section below.) A special case occurs when data expected given a particular medical condition is missing, for example, a white blood cell count in a patient with a fever of unknown origin. Because the lab value is routinely charted in this case, some tend toward considering its absence as a likely indication that it was not done while others tend toward unknown. While the choice between these two labels for missing data does not matter clinically, to assure consistency and prevent later work in the Source Data Verification or data cleaning processes, CCGs should indicate which to choose. [VI]
Uncertain information occurs when the medical record contains vague language or vague notation of clinical information. Such language is often a reflection of the uncertainty present in clinical situations and medical decision-making. Examples include measured values stated as a range or limit such as “blood glucose > 300 mmol/L” in a case where multiple measures were taken, variability was noted but it was clear that the observed values were in the high and range. CCGs should indicate how uncertain quantitative information should be recorded and how multiple measures should be handled in the case where more than one value would meet the criteria for the singular field on the form. Clear instruction on which value should be chosen such as “the peak (or trough or average) value within the period” or “the first (or last or middle) value of the period.” A similar situation surrounds designations of symptoms and diagnoses. For example, a CRF may require a yes/no response for “Positive fecal occult blood” but the medical record states, “dark tarry stool” or “scant bright red blood reported with last bowel movement,” or a patient may report feeling “hot” for the past two nights and “sweating” but did not measure a temperature yet the CRF requires yes/no indication of fever within two days of admission. Such cases also occur in clinical diagnosis where early in the diagnostic process for example, the record may state a Bipolar diagnosis and state possible psychosis, an emergency department work up for chest pain might be documented as possible myocardial infarction in which case later confirmation (or not) would be expected elsewhere in the chart. Such variability and uncertainty can be expected in clinical documentation in many therapeutic areas. The data management goals here are two-fold: (1) accurately reflecting the uncertainty and (2) consistency in how the uncertainty is reflected in the CRF. CCGs should indicate how such foreseeable uncertainty should be recordable on the CRF because it is reflective of reality. [VI] Uncertainty in attribution of a symptom to a disease, identifying the initial clinical manifestation, and identifying a precipitating event are common and instruction is required to achieve consistency in the abstraction process.
Inconsistent information occurs in the medical record when two reports from the same or different reporters, measurements, places in the record fail to agree. Given the extent to which data are pulled forward from one assessment to another, summarized, re-reported, measured by a different method, or documented by a second observer, we should expect medical records to contain many inconsistencies. CCGs should anticipate important data for which such inconsistencies may occur and provide instruction as to which value to choose.[VI]
Errors also occur in the medical record. Given common practices indicated above, some data values in the medical record such as information in discharge summaries and clinical notes will have undergone several transformation steps.
In all of these cases, study leadership can set any categorization, convention or decision rule to be followed in abstracting data. Such categorization schemes, conventions, and decision rules are arbitrary and chosen based on the type of data, and the purpose of the study. As long as these are set a priori, scientifically valid, bias free, logically consistent, reasonable to implement, reproducible, clearly stated in the CCGs, and are applied diligently, they will increase consistency of the abstraction and provide traceability.
The examples in this section emphasize the need for practicing clinicians to be involved in development of CRF completion instructions, for data managers to be familiar with the clinical documentation practices in a therapeutic area, and for study staff at multiple centers to test forms and completion instructions. [VI]
Include clear and precise instructions on where external data such as bottle numbers, kit numbers, or accession numbers are to be located. A description of the number should be included; for example,” the 10-digit kit number is located in the upper right-hand corner of the kit.” Include a visual example so that the information can be unambiguously identified.
For each CRF field, a field definition (operational definition) should be provided where needed to reduce ambiguity.
All of the information needed to understand the question should be on the form including basis of comparison, e.g., “over the last 24 hours,” “since the last visit,” assessment, time points and units of measure, precision and number of significant figures, measurement method.
For emergency medicine and inpatient studies, careful definition and instruction must be given regarding important study patient milestones. Designation of the timing of an index event such as occurrence of cancer, myocardial infarction, stroke, bleeding, or a psychotic episode may seem simple, but there are multiple choices such as symptom onset, first treatment, or hospitalization. However, these may be nuanced in clinical settings; for example, is new onset ischemia or myocardial infarction within 24 hours of a coronary intervention a new event or a complication of treating the initial event?
There are multiple reasons why a datum might be missing. Because one of these reasons is oversight, and because data are usually important to be collected, instances of missing data are usually checked. CCGs should provide clear direction or a mechanism to document the reason for a missing datum.
CCGs should include or reference the time and events table and clearly specify the minimum data required for screen failures, early terminators and lost to follow-up patients. Any additional special data collection rules for these and similar situations should also be provided. Some EDC systems may provide special functionality for controlling the visibility of pages once a subject is indicated as an early-terminator missing.
CCGs should include instructions on how to mark empty pages and any scenarios that require different handling of empty pages. For paper studies, the CCGs should further specify disposition of empty pages such as sending them to the data center with the headers completed and otherwise marked empty or leaving them in subject binders to be retrieved and reconciled at close-out. Some EDC systems may provide special functionality for associating a missing page with a reason why it is missing or for marking a missing page.
For EDC studies, some organizations find it helpful to include instructions on steps required for the monitor to take in order to indicate that source data verification has been completed. Likewise, details for adding, canceling, answering, and closing queries are helpful if the role that is expected to perform monitoring has these rights within the system. While the former is merely informative to sites regarding how monitoring will occur and be documented, the latter includes steps that site personnel are required to take and should be available to sites in CCGs or other documentation. [VI]
Although site personnel are not usually responsible for transcribing or entering data from a patient completed questionnaire, instructions for such may be included in CCGs. [VI] When transcribing, entering or managing patient-reported data, changes should not be made unless agreed procedures and conventions exist and are exhaustively documented.
For EDC studies, if data are integrated from external sources it may be helpful to communicate the expected frequency of the data integration. Clarifying the data points that will not be enterable by site personnel and providing details as to when such data will be available through the EDC system and how to report or respond to reported discrepancies in external data should be included within this section of the guidelines. [VI] Please see the EDC and Integration of External Data chapters for more information, including recommendations, minimum standards, and best practices.
Forms requiring Investigator signature should be specified in the CCGs. [VI] Although not all CRFs may require signature, the details provided to the investigators should remind them that they are ultimately responsible for all data submitted within the subjects’ casebooks. [VI]
For EDC studies, instructions on steps required for investigators to apply their electronic signatures should also be provided. [VI] Details for removing a signature or how data modifications may necessitate re-signing are also helpful tips to consider including.
A contact for questions and clarifications should be identified within the CCGs. [VI]
Section 5.0.1 of ICH E6 states that, “During protocol development the Sponsor should identify processes and data that are critical to ensure human subject protection and the reliability of trial results.
Creation, approval and change control of CCGs [I]
Training investigators, site staff and monitors on CCGs [I]
This revision is based on a systematic review of the peer-reviewed literature indexed for retrieval. The goals of literature review were to (1) identify published research results and reports of evaluation of new methods regarding CRF Completion Guidelines and (2) identify, evaluate, and summarize evidence capable of informing the practice of CCG creation, maintenance, and implementation.
The following PubMed query was used:
(“form completion” OR “CRF completion” OR “CRF guidelines” OR “data collection guidelines” OR “medical record abstraction form” OR “chart review form” OR “chart review form”)
The search query was customized for and executed on the following databases: PubMed (78 results), CINAHL (1 results), EMBASE (156 results), Science Citation Index/Web of Science (3 results), PsychSOURCE (0 result), Association for Computing Machinery (ACM) Guide to the Computing Literature (not searched due to lack of dependence on CCGs on computers), the Institute of Electrical and Electronics Engineers (IEEE) (0 results). A total of 238 works were identified through the searches. The searches were conducted in February. Search results were consolidated to obtain a list of 208 distinct articles. Because this was the first review for this chapter, the searches were not restricted to any time range. Literature review and screening details are included in the PRISMA diagram for the chapter, which follows the references.
PRISMA* Diagram for CRF Completion Guideline Chapter.
*PRISMA is the acronym for the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Two reviewers used inclusion criteria to screen all abstracts. Disagreements were adjudicated by the writing group. Twenty articles meeting inclusion criteria were selected for review. Two individuals reviewed each of the twenty selected articles and the eight additional sources identified through the review. Each was read for mention of explicit practice recommendations or research results informing practice. Relevant findings have been included in the chapter and graded according to the GCDMP evidence grading criteria described in
The additional file for this article can be found as follows:
Example CRF Completion Guidelines. DOI:
Date | Revision description |
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September 2002 | Initial version of the CRF CCG chapter |
May 2007 | Revised for style, grammar, and clarity. Substance of chapter content unchanged. |
June 2008 | Revised for content, style, grammar, and clarity |
December 2019 | Complete revision based on systematic literature review |
The authors have no competing interests to declare.