Automating the Detection of Adverse Events

Adverse event (AE) reporting in the U.S. is largely voluntary, yet it forms the foundation for the detection of post-marketing safety signals that were not identified in clinical trials. It is generally recognized that only a small percentage of AEs get reported. This is certainly my experience in clinical practice. There simply wasn't time to report them all. I reported only those that were the most serious and clearly not described in labeling.

The deployment of Electronic Health Record (EHR) systems nationwide provides a tremendous opportunity to increase reporting. One area that interests me is the potential for EHRs to automatically detect an AE. This requires an unambiguous and computable definition of an AE. I'm not suggesting that EHRs replace a clinician's role in the process, but the potential to automate many steps that the clinician now performs manually is clearly in the best interest of public health.

In a recent post, I discussed how adverse events (AEs) are defined and modeled in BRIDG. I've been doing more reading on this topic and continue to have discussions with others on this important concept. The existing BRIDG definition closely reflects the definition provided in U.S. federal regulations (see 21 CFR 312.32(a)), which states the following:

Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.

The BRIDG definition is:

Any unfavorable and unintended sign, symptom, disease, or other medical occurrence with a temporal association with the use of a medical product, procedure or other therapy, or in conjunction with a research study, regardless of causal relationship. 

The BRIDG definition is appropriately broader. Both contain the concept "medical occurrence." But what is a medical occurrence? How can an EHR detect "medical occurrences?" We're not quite there yet in establishing a computable definition for an AE. But I think we are close.

The Free Medical Dictionary defines occurrence as "any event or incident." The BRIDG definition includes "unintended sign, symptom," which are clinical observations and I think can be considered  incidents. Can a clinical observation be an adverse event? I think the answer is No. The observation needs to undergo an assessment by a qualified individual, such as a health care provider, to establish that:

1. The observation is indicative of the presence of a medical condition
2. The onset (or worsening) of the medical condition occurs after a medical intervention (e.g. drug administration)

Only when these two criteria are met can an one identify an adverse event. What do I mean by a medical condition? The Free Medical Dictionary provides an excellent definition:

medical condition

A disease, illness or injury; any physiologic, mental or psychological condition or disorder (e.g., orthopaedic;visual, speech or hearing impairments; cerebral palsy; epilepsy; muscular dystrophy; multiple sclerosis; cancer; coronary artery disease; diabetes; mental retardation; emotional or mental illness; specific learning disabilities; HIV disease; TB; drug addiction; alcoholism). A biological or psychological state which is within the range of normal human variation is not a medical condition. 

Medical condition is a phrase used in documents for physicians applying to licensing agencies (e.g., state medical boards, malpractice insurancecarriers, third-party payers, etc.), which is used to determine a physician’s physical “suitability” to practise medicine.

What is a medical intervention? I mean any activity (e.g. drug administration, surgery, radiation, device implantation, etc.) undertaken to treat, prevent, cure, mitigate, diagnose, or induce a medical condition.

It is clear that a temporal association with a medical intervention is necessary to establish an AE, so I expect general agreement with the second criterion. Note that a causal relationship is not necessary. The first criterion is where there may be disagreement. Here are a some examples where just relying on an observation to establish an AE is problematic. 

A patient is started on Drug X for a valid indication. The patient has no prior history of hypertension. He also happens to be morbidly obese. A week later, the nurse measure his BP at 155/100 mmHg. Is this an adverse event related to Drug X? I would argue it is not, because an assessment hasn't been done to establish that the patient does indeed have hypertension. In this example, the nurse used a normal sized BP cuff, which is well known to give falsely elevated BP readings in morbidly obese patients. When the BP was repeated using a large BP cuff, the readings were repeatedly within the normal range. 

Let's now say that the patient also had a serum chemistry panel and the serum potassium came back elevated at 5.5 mg/dL (normal for the lab is 3.5-5.0 mg/dL). Is this an AE? Again, for the same reason, an assessment is necessary to establish the presence of an underlying medical condition, in this case hyperkalemia. In this example, examination of the biospecimen sent to the lab indicated the presence of hemolysis. It is well known that hemolysis can spuriously raise a serum potassium measurement due to the high concentrations of intracellular potassium in erythrocytes. The chemistry panel was repeated making sure hemolysis was not present in the biospecimen and the serum potassium was in the normal range. 

The following week the patient was involved in a motor vehicle accident (MVA). Is the accident an adverse event? Again, an assessment is needed. Additional observations might reveal that the patient was sleepy at the time. Hypersomnolence, a new onset medical condition, would be a valid AE that may have precipitated the MVA, but the MVA itself is not the adverse event. 

So my computable definition of an adverse event is:

a new onset medical condition that begins after a medical intervention OR a pre-existing medical condition that worsens after a medical intervention

This definition allows a program in an EHR system to identify adverse events automatically if the medical conditions and interventions are appropriately coded. Clearly there is a time interval component that must also be defined. It would be silly to report a new medical condition that happened years after taking a short-acting drug. One can establish guidelines for a reasonable time interval between the intervention and the medical condition. These should take into consideration things like the pharmacokinetic and pharmacodynamic properties of a drug intervention. Longer time intervals between the intervention and medical condition will increase false positives with regard to the causality assessment, and vice-versa, so the right time interval must be chosen wisely.

From a modeling perspective, I think an Adverse Event is a subclass of a Medical Condition. Medical conditions are the results of assessments of observations, and the definition of an adverse event should be modified accordingly to reflect these relationships. I think this will help pave the way for automatic detection of AEs within EHRs.