A Successful Model and Visual Design for Creating Context-Aware Drug-Drug Interaction Alerts

Abstract Evaluating the potential harm of a drug-drug interaction (DDI) requires knowledge of a patient's relevant co-morbidities and risk factors. Current DDI alerts lack such patient-specific contextual data. In this paper, we present an
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  A Successful Model and Visual Design for Creating Context-Aware Drug-Drug Interaction Alerts Jon D. Duke, MD, MS 1,2 , Davide Bolchini, PhD 3   1 Regenstrief Institute, Indianapolis, IN 2 Indiana University School of Medicine, Indianapolis, IN 3 Indiana University School of Informatics, Indianapolis, IN Abstract  Evaluating the potential harm of a drug-drug interaction (DDI) requires knowledge of a patient’s relevant co-morbidities and risk factors. Current DDI alerts lack such patient-specific contextual data. In this paper, we  present an efficient model for integrating pertinent patient data into DDI alerts. This framework is designed to be interoperable across multiple drug knowledge bases and clinical information systems. To evaluate the model, we  generated a set of contextual DDI data using our local drug knowledge base then conducted an evaluation study of a prototype contextual alert design. The alert received favorable ratings from study subjects, who agreed it was an improvement over traditional alerts and was likely to support clinical management and save physician time. This  framework may ultimately help reduce alert fatigue through the dynamic display of DDI alerts based on patient risk.   Introduction Computerized physician order entry (CPOE) systems frequently employ clinical alerts as a means to influence  physician prescribing behavior with the goal of improving patient safety. 1-4  Such alerts can take a number of forms, from allergy warnings to overdose checking, but among the most widely implemented are drug-drug interaction (DDI) alerts. These warnings are designed to guide physicians in the appropriate monitoring, modification, or discontinuation of potentially interacting medications. Yet despite their widespread use, the potential value of DDI alerts has been limited by low rates of physician compliance. 5,6  Doctors disregard the vast majority of drug interaction warnings, with 49%-96% of all such alerts overridden by the prescriber. 6-9  One explanation for this high override rate is the issue of ‘alert fatigue’, in which physicians become less attentive to warnings in the setting of frequent, low-specificity alerts. 2,10  Improving the specificity of DDI alerts may in part be achieved by identifying a subset of ‘clinically significant’ interactions and eliminating less critical alerts. Initiatives are currently underway to derive such a subset through expert consensus. 11  Yet assessing the clinical significance of a DDI is difficult in the absence of patient context. 12  An interaction of little relevance to one patient may be of great relevance to another. Ideally, a clinical decision support system would utilize patient context to dynamically alter the presentation of DDI alerts to highlight patients at higher and lower risk. Achieving this goal requires integration of pertinent, patient-specific data into interaction warnings. At present, the content of a DDI alert remains independent of patient characteristics, with the same information shown regardless of differences in patient age, co-morbidities, or medication history. We sought to address this gap, and in the following paper we present a model for creating customized, patient-specific drug interaction alerts through the dynamic integration of relevant clinical data. Background The integration of patient-specific data into clinical alerts is a well-established strategy in clinical decision support (CDS). 2,13  Studies have shown that the delivery of relevant patient laboratory results at the time of medication order entry (e.g., displaying creatinine when ordering gentamicin) can improve compliance with drug dosing recommendations. 3,14  Similarly, providing pertinent laboratory results on initiation of a new long-term medication (e.g., showing liver functions tests when ordering a statin) has been shown to improve compliance with drug monitoring. 15  For such interventions to succeed, however, clinicians and information system developers must work together to define what data elements are considered relevant within the context of a given order. For example, a  potassium value may be of great importance when ordering one medication (e.g., lisinopril) but have no relevance when ordering another (e.g., fluoxetine). Thus, for each medication or triggering order, a unique set of pertinent data elements must be defined. 339  Drug-drug interaction alerts operate under the same principle. In the setting of a potential interaction, what patient data is of interest to a physician will depend on the particular drugs involved and the associated adverse effects. Thus, to create DDI alerts containing meaningful patient-specific content, these relevant data elements must be defined for each interaction. Creating these definitions is not a simple undertaking however. We must consider the inconsistent format of existing drug interaction knowledge as well as sheer volume of interactions to be addressed. Most CPOE systems rely on DDI data provided by a handful of large knowledgebase vendors. While the individual data elements that comprise a DDI alert vary slightly from one vendor to the next, the majority of alerts contain the following components: interacting drugs, severity of interaction, clinical effects, predisposing conditions,  pharmacologic mechanism, recommended actions, and references. 16  This information is generally provided in text-format rather than as coded “computable” data, and it lacks conceptual mappings to standardized terminologies such as SNOMED-CT. Due to this lack of standardization, a wide range of terms may be used to describe a given clinical effect. For example, a number of drug interactions may cause bleeding in a patient; but this effect is described variably as ”hemorrhage,” “bleeding risk,” “coagulation defect,” and so forth. The lack of consistent terminology makes it difficult to aggregate all interactions of a certain type. Such aggregation is of value because it allows the “batch” assignment of relevant data elements to entire classes of interactions rather mapping one interaction at a time. For example, we may wish to designate liver function tests as a “relevant lab” for all DDIs known to cause liver damage. But without a standard term for liver damage, we cannot aggregate this group of interactions in an automated fashion. Another significant challenge is the sheer number of interactions to be reviewed. Typical DDI compendia list well over 1000 drug interactions. 16  For example, Drug Interaction Facts contains 1772 listings while the National Drug Data File contains 1846 DDI monographs. 17,18  These numbers will continue to increase as new DDIs emerge in the literature. Given this large and growing body of information, attempting to define relevant data elements for every interaction is a daunting task. One approach is to focus solely on interactions labeled as ‘severe,’ yet prior research has shown a wide variability among drug information compendia in defining severity. 16,19  Furthermore, interactions of even moderate severity may be clinically significant depending on patient context. Thus, we ideally want to assess the full breadth of known interactions but to do so in an efficient manner. In the current paper, we address the aforementioned challenges by presenting a generalizable, sustainable model for integrating patient-specific data into drug-drug interaction alerts. This framework is known as the context-aware drug-drug interaction (CADDI) model and is designed to be interoperable across multiple drug knowledge bases and clinical information systems. We will describe the process for mapping drug interactions to relevant clinical data elements then present a web service that utilizes these data to generate patient-specific DDI alerts. Finally, we will report the results of an evaluation study of a prototype CADDI alert design. Methods  Drug Knowledge Source As the source of our drug interaction data, we used an in-house knowledge base developed and maintained by Regenstrief Institute for use in its CPOE system (‘Gopher’). This database is regularly reviewed and updated by a  pharmacy team and has been an integral part of Gopher’s decision support operations for over 25 years. The database contains 601 distinct DDIs, including interactions between individual drugs and between drug classes.  Mapping Strategy We sought to assign to each DDI a set of concepts specifying the patient data elements to be displayed when the alert is triggered. Rather than making these assignments on a per-DDI basis, we performed batch assignments according to clinical effect. So for example, all drug interactions causing ‘bleeding’ would be associated with relevant concepts such as hemoglobin, platelets, and PT/INR. To identify and standardize the effects of each interaction, we utilized the Medical Dictionary of Regulatory Activities (MedDRA), a hierarchical terminology used in drug safety. Because MedDRA contains some non-clinical concepts, we first reviewed the 76 MedDRA semantic types and eliminated 44 that were felt unlikely to be associated with adverse effects. Using the remaining 32 types, we selected 51599 MedDRA terms as our core set of clinical concepts. We then used natural language processing (regular expressions and stem matching) to search for these concepts in the ‘clinical effect’ section for each interaction in our knowledge base. We identified MedDRA terms in 489 of 601 interactions, with a total of 93 340  unique clinical effects represented. Table 1 shows the 12 most common effects, accounting for 199 (33%) of the interactions in our database. Table 1. Most common clinical effects extracted from drug interactions in the Gopher database.   For 11 of these 12 clinical effects (‘death’ was excluded), we selected a set of relevant data elements appropriate for display at the time of physician alerting. Data elements were grouped into two categories: relevant tests and  predisposing conditions. Tests were coded to the Logical Observation Identifiers Names and Codes (LOINC) terminology. Conditions were coded to Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT). Figure 1 shows an example of the interactions, concepts, and relationships for the clinical effect ‘rhabdomyolysis’. Clinical Effect # of DDIs Arrhythmia 35 Increased Anticoagulant Effect 27 Torsade de Pointes 26 Myopathy 24 Rhabdomyolysis 15 Digoxin Toxicity 15  Nephrotoxicity 12 Hypotension 11 Hypertension 10 Bleeding 8 Death 6 Cardiotoxicity 5 Hyperkalemia 5 Figure 1. Sample relationships between drug interactions, clinical effects, and related data elements in the context-aware drug-drug interaction (CADDI) database 341   Prototype Service for Delivering CADDI Alerts Once the interactions, clinical effects, and related data were mapped and stored in the database, we designed a  prototype web service for generation of CADDI alerts. For our source of patient data, we utilized the Continuity of Care Document (CCD). The CCD is a patient summary specification based on the HL7 Clinical Document Architecture. CCDs play an important role in health information exchange and are increasingly offered as a format for export of patient data from electronic medical record systems. A fully semantically coded (‘Level 3’) CCD, such as that generated by our institution, provides patient medications, diagnoses, and laboratory results in structured form using standardized terminologies. Figure 2 depicts the steps in the creation of a CADDI alert using the example of an interaction between simvastatin and diltiazem. First, the web service receives as its inputs a patient CCD and a drug interaction identifier (e.g., a Gopher DDI ID). Second, the service uses this identifier to query the CADDI database and retrieve static information about the DDI such as the interacting drug classes, severity level, and clinical effects. Third, based on the clinical effect (e.g., rhabdomyolysis), the LOINC and SNOMED-CT codes for all relevant laboratories and  predisposing conditions are retrieved from the database and passed to a CCD parser. Fourth, the CCD parser uses these codes to search the patient’s record and retrieve any matching labs or diagnoses. Finally, the service combines the static DDI information from the CADDI database with the dynamic patient-specific data from the CCD to deliver an integrated contextual alert.  Prototype Alert Design Having created a model for integrating patient specific data into DDI warnings, we developed and evaluated a  prototype alert design. Few studies have explicitly explored the visual design of drug-drug interaction alerts, but several studies have looked at the design of clinical alerts in general. Feldstein et al found that physicians placed a high priority on alerts being brief, clear, and easy to navigate with minimal mouse clicks. 20  A study by Krall and Sittig found that users were sensitive to multiple keystrokes, excess screen switching, and frequent movement from Figure 2.  Steps in the generation of a context-aware drug-drug interaction (CADDI) alert. 342  mouse to keyboard. 21  Phansalkar et al performed a human factors review of alerting principles and made several recommendations including coding alert priority using color and position, perceptually grouping related information to assist in decision-making, and tailoring alerts to individual patients and users. 22  After considering this literature, we began an iterative alert design process. Our goal was to create a succinct, textually sparse, and graphically strong alert. Our initial designs were refined through critiques by experts in human-computer interaction as well as review by clinical peers. An example of the final prototype design is shown in Figure 3. Usability Evaluation The goal of our evaluation study was to gather clinician perspectives on whether the addition of contextual data to drug interaction alerts would improve physician satisfaction, support clinical management, and save time. We also sought to measure usability factors specific to our prototype including its clarity, organization, and efficiency. Participants consisted of 11 physicians and 1 senior pharmacist. Clinical experience ranged from 3 to 20 years, and all subjects except the pharmacist were currently engaged in clinical practice and were seeing patients at least one-half day a week. All subjects had prior experience with CPOE and electronic reminders. The usability evaluation consisted of task analysis using a think-aloud protocol. Subjects were informed that they were participating in an evaluation of a new clinical alert design and were thus aware of the focus of the study. After providing consent, the subjects were presented with an interactive mock CPOE interface and instructed to prescribe a set of medications for two different sample patients. During the course of ordering these medications, two contextual DDI alerts were triggered and displayed to the subject. The displayed alerts were embedded in the prototype environment and not generated dynamically via the CADDI web service. The triggering pairs of medications were 1) azithromycin and warfarin and 2) verapamil and simvastatin. Figure 3. Prototype design of a context-aware drug-drug interaction alert.   343
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