1. Most Common Issues in Define.xml files
NJ CDISC User Group
Sergiy Sirichenko
October 21, 2015

2. Abbreviations CT – CDISC Control Terminology
VLM – Value Level Metadata

3. Major problems in Define.xml
Usage of outdated Define.xml v1.0
Inconsistency in metadata
Missing study specific metadata
Lack of expertise

4. Outdated Define.xml v1.0 is still used
Define.xml has many standard limitation issues
“The first” versions are never perfect
Define.xml v1.0 is 11 years old
Does anybody still using SDTM IG 3.1.1?
Define.xml v2.0 is robust enough to handle current submission needs
Separate presentation or webinar will be dedicated to this topic

5. Lack of structural consistency in v1.0
Metadata structural consistency in define.xml v2.0 is preventive against errors
Example: Variable Source value defines other attributes
“CRF” -> Pages are expected
“Derived” -> Computational Algorithm is expected
Define.xml v1.0 allows entering CRF pages for derived variables, having missing values for expected attributes, etc.

6. Limited and confusing VLM in v1.0
In v1.0 Value Level Metadata does not provide a reference to variable it applies
Cannot handle multiple conditions
Confusing and complex hierarchical VLM structure is used instead
Example:
LB domain has VLM assigned to LBCAT
LBCAT has VLM for LBSPEC, LBSPEC -> LBMETHOD, etc.
Properties of LBORRES (or other?) variable are described on some point of this tree structure
V2.0 has explicit single expression with multiple condition assigned to particular variable

7. Some sponsors try to mimic v2.0
To use functionality of v2.0
Example:
V1.0 does not have attributes for NCI Codes
Sponsor added NCI Codes as a part of Decode value
V2.0:
V1.0:
It’s invalid usage of v1.0 standard!
Why not switch to v2.0 instead?
Permitted Value (Code)
mmol/L [C64387]
ng/mL [*]
Code Value
Code Text
mmol/L
mmol/L [C64387]
ng/mL
ng/mL [*]

8. Some sponsors use custom stylesheet
Often done to mimic the functionality of v2.0
Regulatory reviewers like consistency, so please use the CDISC provided standard stylesheet

9. Non-relevant metadata
Variable Role is used for standard development, but does not add any value for study metadata
Example:
STUDYID and USUBJID can only be “Identifier”
Does anyone actually used this info?
Define.xml 2.0 stylesheet doesn’t display it

10. Order of datasets and variables
Alphabetical
Example: AE, CM, DM, …
Correct: logical order as defined by standard - by Class, then by domain name
Random
Example:
Correct: as variables are present in dataset
Order #
Variable
Label 1
AECAT
Category for Adverse Event  2
AEDECOD
Dictionary-Derived Term  3
AEGRPID
Group ID  4
AESEQ
Sequence Number  5
AETERM
Reported Term for the Adverse Event  6
DOMAIN
Domain Abbreviation  7
STUDYID
Study Identifier  8
USUBJID
Unique Subject Identifier  9
AEBODSYS
Body System or Organ Class  10
AEOUT
Outcome of Adverse Event  …

11. Missing or invalid Origin
No references to CRF pages
Example: Origin=”CRF”, instead of “CRF Page 12, 41, 57”
Inconsistencies in Origin/Comments
Example:
RFSTDTC has Origin = “CRF”
No annotations on CRF (as expected)
Comments: “First dose of study medication” (it looks like Derived variable)

12. Missing of invalid Derivations
Example 1:
AGE: ”Calculation: = Min DOV - BRTHDTC in AGEU“
What is DOV? How I can use Character value (BRTHDTC) in arithmetical formula? How were missing or partially missing dates handled?
Derivations should be provided in terms of available data
Example 2:
“ZX021_AE_DURATION”
???

13. Invalid Value Level Metadata
VLM should be described on the same level as regular variables:
Codelist, DataType, Length, Origin, Derivation, etc.
Common issue is missing or invalid metadata for Value Level
Consider VLM as new variables with properties independent from “hosted” variable
Example: Treatment Emergent Flag in SUPPAE has length=1, not 200 as QVAL variable

14. Duplicate records
Code List
Term
Variables
Order Number

15. External dictionaries
Info on external dictionaries (MedDRA, WHODrug) is not provided correctly
As comments to variable (non-machine readable)
ISO8601 is defined as External Dictionary
It’s a data format associated with all date, datetime, etc. variables. No specific reference to ISO8601 is needed if Data Type is defined correctly

16. Missing study specific metadata
Study specific information is crucial for reviewers
However in most submission packages it’s missing
Value of define.xml, SDRG, aCRFs is to explain what is unique in this particular study

17. Missing Codelists
Codelists are limited to variables which are assigned to standard CT
Commonly missing study specific Codelists for variables
Category (--CAT), Subcategory (--SCAT)
EXTRT, ARMCD, --TESTCD/--TEST, QNAM, TPT
RDOMAIN in CO and RELREC domains
XXTOX, …

18. Merged Codelists
Due to confusion between Standard CT Codelist and study Variable Codelist
Example:
Define.xml has one codelist (UNIT) assigned to all --DOSU, --VAMTU, --ORRESU, --STRESU variables
This codelist includes all unique terms across all study “units” variables and have 450 items, while for example EXDOSU variable is populated with one “mg” term only
A reference to 450-terms codelist is not relevant

19. What is define.xml Codelist?
Define.xml Codelist describes data collection process and should be limited to all terms used for data collection of specific data element (a particular Variable or Value Level)
For example, LBSTRESU, EGORRESU, EXDOSU usually have separate Codelists based on the same (UNIT) standard CT
If data is collected as a free text, then Codelist may be not applicable
Common example is CMDOSU, CMDOSFRQ, CELOC, etc.

20. Missing terms in Codelist
Term is present in data
SD0037 check
Programming error
Due to misspelling , leading space characters, etc.
Due to missing Decoded value for some items
CodeList vs. EnumaretedItem
Codelist was populated based on collected data, but some options from CRF page are not included
Example: Only race “WHITE” is collected, while 6 options are present on CRF

21. Missing or invalid Value Level Metadata
Content of SUPPQUAL domains must be described

22. Missing description of --SPID
--SPID is often Key Variable in domain
Clear and detailed description is required to understand study data
Why --SPID was introduced? How it was derived? …
Often Sponsors copy Notes text from CDISC IG. It’s completely invalid approach! Study specific information is expected.
SDTM IG text: “Sponsor-defined reference number. Perhaps pre-printed on the CRF as an explicit line identifier or defined in the sponsor’s operational database. Example: Line number on a CRF Page.“

23. Missing description of variables
Study specific variables are the most important
RFPENDTC, RFSTDTC, RFXSTDTC, --GRPID, --LNKID,--SPID, …
SDTM text is not a variable description!
See --SPID slide as an example

24. Invalid Key Variables Too long list of variables
Example: “STUDYID, USUBJID, EXSPID, EXTRT, EXCAT, EXDOSTXT, EXDOSU, EXDOSFRM, EXDOSFRQ, EXDOSTOT, EXROUTE, EXSTDTC, EXENDTC, EXSTDY, EXENDY, EXTPT,EXTPTNUM, EXTPTREF, VISIT”
Inconsistency between Key Variables and domain Structure
Example: Structure: “One record per event”
Key Variable: “USUBJID, AETERM, AEDECOD, AESTDTC, AESEV, AESER, AEACN, VISIT”
Usage of –SEQ as Key Variable
Example: “USUBJID, AESEQ”

25. Non-compliance with eCTD
Define.xml file is located in different folder than datasets
Example:
define.xml in …\tabulation
Data in …\tabulation\sdtm
File name is not “define.xml”
“define_study_001_sdtm.xml”

26. Contact info:
Sergiy Sirichenko