Activity Start Rules in Study Protocols

Imagine a software tool that reads a study protocol, can analyze the data collected on any subject to date and determines what activity to perform next. Imagine all of the data collection errors and protocol violations that can be avoided by following the instructions from such a tool. From a regulatory perspective, imagine running an analysis that describes in sufficient detail whether a protocol was conducted properly and can automatically determine where protocol violations occurred. This is possible if we have machine-readable start rules for study activities.

I recently wrote about Study Rules. Today I continue that discussion by looking at Start Rules and how to represent them computationally in the RDF (Resource Description Framework)  to enable the tools described above.

The start rules are rules that determine if an StudyActivity can begin or not.  The start rule describes the condition(s) present in the collected data that must be met for a StudyActivity to begin. If the condition is met, the StartRuleOutcome is true and the activity may begin. If the condition is not met, then the outcome is false.

All study activities have start rules, although they may not be explicitly stated in the protocol.  Often the start rule can be restated more explicitly. It is also useful to consider a "default" start rule which is always true (i.e. the condition to start the activity is always automatically met) and therefore the Activity can begin anytime. The very first activity in a study, usually "ObtainInformedConsent" can begin anytime. Its start rule is the default start rule. The start of the "ObtainInformedConsent" activity also marks the start of the Screening epoch (activity). Screening is a composite activity (i.e. made up of multiple sub-activities) whose start rule says begin Screening when the ObtainInformedConsent activity begins.

Start Rules can describe not only whether the activity can begin, but when it can or cannot begin relative to another activity. There are different types of start rules.

1. A "Prerequisite Start" Rule (PRST) allows the target activity to begin when the prerequisite activity has started. 
2. A "Prerequisite Complete" Rule (PRCO) allows the target activity to begin when the prerequisite activity is completed, regardless of the outcome. 
3. A "Prerequisite Outcome" Rule (PROUT) allows the target activity to begin when the Prerequisite activity is complete and has a certain outcome or result. 

Start rules may be associated with a protocol-specified delay.

1. A delay = 10 mins means wait 10 minutes after the start condition is met before performing the activity. 
2. A maximum delay = 10 mins means wait no longer than 10 minutes before starting the activity. 
3. A minimum delay = 10 mins means wait at least 10 minutes before performing the activity.

Certain planned activities can be skipped altogether if a certain condition exists. For example, if the sex data collection activity results in Sex=M, then a Pregnancy Test can be skipped. This could be captured in a separate "Skip Rule;" a topic for a future post (or better yet, a start rule for a start rule!). In this case, the start rule can be skipped and the activity becomes a "logically skipped"activity per protocol, and there is no violation.

So a start rule has the following properties/predicates
:prerequisite (links to the prerequisite activity)
:prerequisiteExpectedOutcome (the expected outcome/result for the prerequisite activity.)
:prerequisiteExpectedStatus (the expected status for the prerequisite activity.)
:skipActivity (link to the activity that determines if the target activity can be skipped)
:skipOutcome (the expected outcome of the skip activity that allows the target activity to be skipped
(note: this may be better coded in a separate skip rule)
:ruleDescription (a short textual description of the rule)
:ruleDescriptionLong (a long description)
:subRule (a link to another subordinate rule)
three timing attributes: :delay, :delayMin; delayMax (as discussed above).

How does this look using RDF (the Resource Description Framework)?

I have created a "dummy" clinical trial for migraine prevention that starts with the InformedConsent activity and ends up with a randomized treatment activity. During screening, subjects undergo [1] recording the sex of the subject, [2] an RPR test for syphilis, and [3] a pregnancy test, if female.  To be eligible for continued participation, one must have a negative RPR and a negative pregnancy test, if female. Those that are eligible are Randomized to two treatments: LowDose 10mg daily or HighDose 20mg daily.  Those randomized are given study medication to prevent their migraines.

First we link the activities to the subjects:

data:Person_1  
        rdf:type smm:Person ;

        smm:participatesIn       
                  data:Observation_Sex_1 , 
                  data:Observation_RPRTest_1 ,               
                  data:randomization_BAL2_1 , data:ProductAdministration_1 , 
                  data:InformedConsent_ADULT_1 , data:Observation_PregnancyTest_1. 

Then we link a start rule for each activity. In the table below the predicate (not shown) is smm:startRule.

Except for the default start rule, which says the activity may begin at anytime, each start rule has a prerequisite activity (one that must take place before the target activity. In our example, the rule for the pregnancy test checks to see if the patient is Female (i.e. does the Sex recording activity document Sex = F? If yes, then the rule is triggered (outcome = true) and the test is tagged for execution.  If the Sex = M then the rule outcome is "not applicable" since the test is not typically performed on male subjects.

Notice that the RPR Test and the Sex observation Test both have the same start rule, which requires that InformedConsent be complete with Outcome InformedConsent_GRANTED. Both tests become eligible for execution simultaneously.

Once all the screening activities have been conducted, the next activity "Eligibility Determination" is triggered and has a binary outcome: True (subject is eligible to continue) or False (subject may not continue). This Eligibility Determination activity is in fact the Start Rule for the Randomization activity. This web of inter-related activities is ideally represented in a graph and makes it quite easy to manage study conduct and monitor the trial for protocol violations.