Thursday, August 20, 2015

EPOCH expected in most SDTM domains - why that is nonsense

The FDA is over and over again complaining about the file sizes of SDTM submissions, and forcing sponsors to squeeze these files as much as possible. However, the FDA does not allow us to submit zipped files, but they cannot give us a reasonable explanation why not either.
On the other hand, we see that each time a new SDTM-IG is published, additional derived variables have been added - all on request of the FDA. So no wonder files become so large ...
Some time ago, a lot of new --DY (study day) variables were added and made "expected" and it is now also expected that the "the EPOCH variable is included for every clinical subject-level observation".

Now both --DY as EPOCH are derived. --DY (study day) can easily be calculated from the --DTC (date/time of collection or observation) and the RFSTDTC (reference start date/time) in the DM (demographics) domain. Similarly, EPOCH can easily be calculated from the --DTC and the records for that subject in the SE (Subject Elements) domain.

So why does the FDA then still insist that as well --DY as EPOCH is delivered for each observation although it blows up the size of the datasets? Can't the tools of the FDA reviewers calculate the --DY values and the EPOCH "on the fly"?

Some time ago, we developed the "Smart Dataset-XML Viewer", a free and open-source tool for inspecting SDTM, SEND and ADaM files in the new CDISC Dataset-XML format. The Viewer has a good number of great features for exactly doing what the FDA's tools cannot accomplish. It then was a big surprise to us when we were told that most reviewers choose not to use the viewer during the "FDA Dataset-XML pilot". Most of them preferred the (statistical analysis) tools that they always have been working with.

I recently added the newest feature to the "Smart Dataset-XML viewer" which is the display of the (on-the-fly) lookup of the EPOCH and the ELEMENT on each --DTC value. It took me just two evenings to implement that. What the tool is doing is for each --DTC value, it picks up the USUBJID and then compares the date/time with the SESTDTC (Start Date/Time of Element) and SEENDTC (End Date/Time of Element). When the --DTC value falls between the start and end date, the element code (ETCD) is retrieved as well as the value for EPOCH.

Here is a screenshot of a result (here for an observation in the LB domain):

with a detail snapshot:

showing that for the date/time of specimen collection "2014-01-16T13:17" (January 16th 2014 at 1:17 pm) the study day (LBDY) is 15 (15th day of the study for this subject) and the corresponding Element is "PBO" and the corresponding EPOCH is the "blinded treatment" (other epochs are "SCREENING" and "FOLLOW-UP). These values were NOT taken from the dataset, they were calculated "on-the-fly" from the RFSTDTC and the records for this subject in the SE dataset:

This shows that the obligation of the FDA to add --DY and EPOCH to each record is nonsense.
It can easily be done by viewing or analysis tools. The "on-the-fly" calculation even considerably improves data quality.

This nice little feature (again, programmed in two short evenings time) has some further implications. For that, let us have a look at the AE (adverse events). The originally captured dates are AESTDTC (start date/time of adverse event) and AEENDTC (end date/time of adverse event). That's it.
The FDA also requires to submit AESTDY (study day of start of adverse event) and AEENDY (study day of end of adverse event), unnecessarily blowing up the file size again, and even worse, introducing data redundancy. But what about the EPOCH?
Which EPOCH? That for the start of the adverse event? Of the end of it? Or maybe of the date/time of the collection of the AE? It is not possible to add 3 extra columns with EPOCH, or should we add new variables in SUPPAE, for example STAEPOCH, ENDEPOCH? The FDA doesn't tell us.
But of course, for each of them, the "Smart Dataset-XML Viewer" can calculate them "on-the-fly". Here are some screenshots:

First for AESTDTC:


and for AEDTC:

stating that the AE started on study day 3 (element PBO, epoch BLINDED TREATMENT) and ended on study day 199 (element FOLO, epoch FOLLOW-UP) and was captured on day 23 (element PBO, Epoch BLINDED TREATMENT).

So, with this feature, reviewers can easily find out in what study day and in which element and epoch the adverse event started, ended, and was captured in the EDC system, WITHOUT having the --DY and EPOCH variables in the dataset itself.

I will soon upload the updated "Smart Dataset-XML Viewer" programm and source code to the Sourceforge website from which anyone can download them.

Tuesday, August 4, 2015

Define.xml and stylesheets

I have doubted a long time whether I should write this blog entry or not. The trigger then to do it came from an entry in the OpenCDISC forum stating "Can the indentation of items in the sidebar be controlled for all font sizes? Indentations appear normally for small fonts, but become irregular for larger fonts. Technical note: I am viewing define.xml files in Internet Explorer."

First of all, this has nothing to do with OpenCDISC. Probably however, the writer used an OpenCDISC tool to generate the define.xml after having generated the SDTM files (which I consider bad practice) and then viewed the result using Internet Explorer.
The writer of that entry doesn't even seem to realize that  a stylesheet is used for representing the define as HTML in the browser. For him/her, define.xml is what is seen in the browser.

Define.xml is however much more, it contains the metadata of your submission in XML, and not in HTML. So it can and should be used to validate the submission data themselves. Unfortunately, most validators even don't do that. The argument (sic): "Unfortunately the industry compliance with define.XML standard is not high enough to rely on user-provided metadata".

But today I want to discuss a somewhat different topic: stylesheets.

The define.xml specification comes with a sample XSLT stylesheet that was developed by Lex Jansen (SAS), member of the CDISC define.xml development team. It is one of the best stylesheets I have ever seen. Even though, we regularly read complaints from people that they want it ... different. They do not seem to realize (or don't want to) that this is just a sample stylesheet, and that providing a stylesheet (not necessarily the one developed by Lex) is their own responsibility when submitting data to the FDA. So if they want to have changes to the stylesheet, they should make them themselves.

Now, what is an XSLT stylesheet?
A stylesheet transforms the XML into something else. The "T" in XSLT stands for "Transformation" isn't it? In many cases, the transformation is done to HTML (as in the define-stylesheet), but stylesheets can also transform XML into PDF, CSV, text files, SQL, or other XML...
So what the user sees in the browser when (thinking) he/she is opening the define.xml, is principally not the define.xml, but it is the visualization of the HTML that is generated by the stylesheet starting from the information in the define.xml.
So, essentially (and don't misunderstand me), what-you-see-is-not-what-you-have.

Now, Lex's stylesheet is an extremely good one, and it makes most information that is in the define.xml XML file display in a very-user friendly way - you can trust Lex and the define.xml team.

Transformation means manipulation (in the good sense of the word). One can however also use stylesheets to manipulate data in the bad sense of the word. Now, we are all honest people, and we would never never think about changing the define-stylesheet so that the information seen in the browser does not correctly represent what is in the define.xml XML file itself.

That is where the devil in me starts to speak ...

Let us look at a simple example: the "Key" column that is seen in the table where the variables for each dataset are defined. It looks like (here for the DS domain):

The XSLT for it in the define-stylesheet is:

        <xsl:for-each select="./odm:ItemRef">
        <td class="number"><xsl:value-of select="@KeySequence"/></td>

Let us now make a small change to the stylesheet:

        <!-- added J.Aerts -->
        <xsl:variable name="MAXKEYSEQUENCE" select="max(./odm:ItemRef/@KeySequence)"/>
        <xsl:variable name="MAXKEYSEQUENCEPLUSONE" select="$MAXKEYSEQUENCE+1"/>
        <!-- end of addition J.Aerts -->
        <xsl:for-each select="./odm:ItemRef">
<!-- <td class="number"><xsl:value-of select="@KeySequence"/></td> -->
            <xsl:when test="@KeySequence != ''">
                <td class="number"><xsl:value-of select="$MAXKEYSEQUENCEPLUSONE - @KeySequence"/></td>

And what you then see in the browser is:

Do you see the difference? The values for the "Key" have been reversed! I.e. the lowest key number has become the highest and the highest has become the lowest!
But we did not change anything in the define.xml file itself isn't it? We only made a minor change to the stylesheet. Although this is a pretty harmlous example, it demonstrates that the result of a stylesheet does not necessarily represent the source XML data.
Again, we are honest people, and we would never never do something like this, and especially not when submitting data to the FDA.

So what do we learn from this?

- stylesheets should be validated. Does a stylesheet really truly visualize the data from the define.xml?
- it is the sponsor's responsibility (and not the one of Lex or of CDISC) to provide a stylesheet that truly visualizes what is in the define.xml
- the FDA should use its own stylesheets
- what you see in the browser (when a stylesheet is used), is not the define.xml
- the define.xml is a machine readable XML file defining the metadata for a submission and should be used as such
- what you see in the browser is just a human-friendly representation of what is in the define.xml - decisions should not be based on this "view"
- people should stop thinking about define.xml being a replacement for define.pdf
- in submission teams at sponsor companies, there should be at least 1-2 persons with good XML knowledge (it's easy, my students learn it in just 2 x 1.5 hours)

Comments are as always extremely welcome!