I.

XML Grammar Development for System Independent and Reusable Electronic Case Report Form Presentation

시스템 비의존 및 재사용가능 전자증례기록지 표현을 위한 XML 문법개발

Okgu Kim*, Young Shin Kim↗, Seon Ha Kim↕,↗, Hwa Jung Kim↕,↗, Nam-Kyong Choi↕, Jung-Lim Jung↕, Ju Han Kim*,↕, Byung Joo Park*,↕,↗ bgjqp

* Interdisciplinary Program in Bioinformatics, Seoul National University College of Natural Sciences

↕Department of Preventive Medicine, Seoul National University College of Medicine

↗ Seoul National University Hospital Clinical Trial Center

Abstract: Conventional clinical trial management systems manage Electronic Case Report Forms (eCRFs) using specific software packages rather than international standard computer language. This software package dependency limits reusability of eCRF. To solve the dependency problem, we developed eXtensible Makrup Language (XML) based eCRF grammar. By using XML for describing eCRFs, we can implement and share eCRFs among institutions regardless of software packages of clinical trial management system. Describing eCRFs using XML also gives more reusability of eCRFs. Common data elements and common eCRF sections described using the eCRF grammar can be directly embedded into other eCRFs which were also described using the eCRF grammar. The eCRF grammar has been updated to accomodate those paper CRFs not covered at the development time, and the eCRF grammar is being applied to clinical trial management system being developed at Seoul National University Hospital Clinical Trial Center.

Keyword: XML, CRF, CDE, Clinical Trial, HTML

Background

After the draft of human genome sequence published, concerns are now on development of new drugs, especially on clinical trials. Streamlined clinical trial execution is getting important, as time and cost for the execution have been increased. According to the report submitted to Korea Health Industry Development Institute, average time required for clinical trials from phase one to phase three in 1990 to 1996 was 6.7 years, compared to average 5.5 years in 1980s.[1] Clinical trial design step may be the most important step due to its impact on the whole trial execution.[2,3] In the design step, Electronic Case Report Form (eCRF) design and management and its reuse issue have been researched.[4] Conventional clinical trial management systems, such as TrialDB and Clintrial, support reusable eCRF management.[5,6]

The conventional eCRF management systems, however, have limitation because they implemented the management of eCRF using specific software packages, such as Access of Microsoft or PowerBuilder of Sybase. This software package dependency problem impedes sharing and exchanging of parts or a whole of eCRF. We solved this dependency problem using the international standard computer language, eXtensible Markup Language (XML), for describing eCRF. XML is highly flexible and internet-oriented, and provides an open framework for defining standard specifications.[7] We can describe eCRFs using XML, validate using XML Schema language, and translate into other forms, such as HTML, using eXtensible Stylesheet Language Transformations (XSLT). Common Data Elements (CDEs) can be presented using XML and directly embedded into larger part of XML based eCRF. By sharing XML based CDEs or eCRFs, standard data collection can be achieved.

We present a description of our development of eCRF grammar to describe eCRF using XML. Paper CRF collection, concept of atomic element and composite element with presentation tags are first introduced. Next, Unified Modeling Language (UML) class diagram design is described, which is followed by XSLT development for translating eCRF into HTML.

II. Method

The eCRF grammar development process started with collecting paper CRFs from clinical trial studies that we have conducted. The next process was identifying data elements with their type information as well as paper CRF decoration parts, such as tables, special symbols, and static texts. Then, we defined data types that can cover all of the identified data elements, from which we devised concept of atomic element and composite element. We drew UML class diagrams that can be used for XML Schema modeling, which is followed by developing XML Schema. Finally, we developed XSLT to translate eCRF to HTML so that we can see the HTML version of eCRFs translated from XML based eCRFs.

Data Element Collection from Paper CRFs

As the first step of eCRF grammar development, we collected paper CRFs that we have conducted at Seoul National University Hospital Clinical Trial Center (SNUH CTC) since 1997. Paper CRFs were chosen from five representative areas of clinical trial field. They are antibiotics, anti-cancer, anti-hypertension, and anti-psychotic drugs, and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). From the collected paper CRFs, we made a sample paper CRF set for an anti-cancer clinical trial using data elements of the collected paper CRFs. The sample paper CRF set should represent the collected paper CRFs, and should be the one with which we can really study.

The next step was retrieving data elements from the sample paper CRF set. There are eight sections in the sample paper CRF set. They are inclusion/exclusion criteria, visit zero, visit one, visit two, patient summary, adverse event, concomitant medication, and post study follow-up. From each section, we tabularized data elements with name, type, permissible value or range, and notes. Figure 1 shows the table of the data element information entered into an Excel file. From the data element information, we found that five basic types of data element can describe every data element in the sample paper CRF set. The five basic types are text, integer, real number, date, and checkbox. We next tested the five basic types can cover all the paper CRFs collected from the five clinical trial fields described above in this section. The result was that the five basic types also cover all the data elements of the paper CRFs.

Figure . Information of data elements collected from the sample paper CRFs. Information includes name, type, permissible value, and note. Larger texts, such as "1. Inclusion/Exclusion Criteria" are title of sections.

Atomic Element and Presentation Tags Identification

We identified CRF consist of data element part and CRF decoration part. Data enterer, such as clinicians or nurses, write observed value or result on data element parts. CRF decoration parts are static compared to the data elements that accept data from data enterers. Examples of the decoration part are page number, heading, static text, table, special symbols, and directions. The data elements are covered by five basic types and presented in eCRF grammar as atomic elements. Atomic element is an element that has one matching data element in paper CRFs and cannot be decomposed into other data elements. We, therefore, get the same number of atomic elements as the number of identified data elements from the sample paper CRF set described in the previous section.

CRF decoration parts are presented as presentation tags in eCRF grammar. Their main characteristic is static and they are to be presented in eCRFs as fixed parts. Presentation tags are expected to be flexible so that conventional paper CRF layout can be described in eCRF as well. For flexible presentation tag grammar, we decided to consult the tags of HTML 4.1. Minimum set of tags of HTML was applied to eCRF presentation tag grammar. This consultation was also applied to the development of XSLT used to translate XML based eCRF into HTML version of eCRF.

Composite Elements

Composite element concept has been devised to bind atomic elements and presentation tags, recursively. Composite element, therefore, is a set of atomic elements, presentation tags, and other composite elements. By this way, certain parts of eCRF can be presented as one composite element. Atomic elements and composite elements can be a means for sharing and exchanging CDEs and common eCRF sections (CCSs) of eCRF. CDEs and CCSs described using XML based eCRF grammar are registered to a web site and can be directly embedded into other eCRFs.

UML Class Diagram Design and eCRF Grammar Development

UML class diagram can express structural relationships among classes. We used UML class diagram to identify hierarchical relationships among basic types and common attributes that can be presented in more abstract classes. Drawing UML class diagrams also streamlines the process of eCRF grammar development because XML Schema language accepts hierarchical presentation. Figure 2 shows the part of class diagram that was developed from the collected data element types.

Figure . UML class diagram about atomic elements with relationships.

Translation of UML class diagrams into eCRF grammar using XML Schema was straightforward. Classes and relationships in the class diagram were presented as elements and their relationships in the eCRF grammar. To test the eCRF grammar, the sample paper CRF set was translated into eCRF set according to the developed eCRF grammar. The eCRF grammar has been improved to accommodate more presentation tags that were not included in the sample paper CRF set but considered important to make eCRF more flexible. It is now at version 3.0.

XSLT Development

While eCRFs are described using XML based eCRF grammar, they have to be translated into HTML for data enterers to see the actual eCRF. As described above, presentation tags were designed with consultation to HTML tags. Presentation tags in the eCRF grammar, therefore, have matching HTML tags. These matching information are used in translating presentation tags. Atomic elements are translated into input tags of a form tag in the generated HTML. The form tag occurs in the HTML only once.

III. Result

The developed eCRF grammar has been tested to the sample paper CRF set, then tested to every collected paper CRFs. We found that the developed eCRF grammar can describe paper CRFs we are currently archive. One sample paper CRF to be described into eCRF is shown in Figure 3. Figure 4 shows HTML output translated from the eCRF of the sample paper CRF shown in the Figure 3. The XML Schema file of the eCRF grammar has six atomic elements, which are text, textarea, integer, real, date, and checkbox. Presentation tags include alignment tags, text effect tags such as bold and italic, special characters such as degree Celcius, multiple spaces, and arrows, line break tag, and table tag with column and row control tags. New presentation tags have been added for better HTML version of eCRF.

Composite element can describe sections of eCRF. We identified that in eCRFs there are sections that are common to several clinical trial fields. Examples are demography, concomitant medication, and follow up. These sections have common data elements that do not change among the clinical trial fields. We first identified common sections and described them as common eCRF section or CCS. Then, we identified CDEs in the CCSs. Finally, we checked that the developed XSLT for translating XML based eCRF into HTML version of eCRF works. By using Xalan library 2.6.0 of Apache Group, XSLT processor translates eCRFs without any problem into HTML.

IV. Conclusion

Figure . Sample paper CRF to be described into eCRF using the developed eCRF grammar.

Development of eCRF grammar for describing paper CRFs performed at SNUH CTC was successful. We could define basic types that cover all the data elements of the paper CRFs, and could define atomic elements in eCRFs for data input. We also could identify paper CRF decoration part, and then implemented presentation tags for describing eCRF decoration part. Division of CRF into atomic elements and presentation tags make our eCRF grammar be flexible in describing eCRFs.

Acknowledgements

This research is part of the National Research Laboratory Project M10302000093-03J0000-04710 funded by Korean Ministry of Science and Technology.

References

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Figure . HTML version of the sample paper CRF shown in the Figure 3. eCRF is first generated based on sample paper CRF and then translated into HTML.

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