Mining Adverse Drug Reaction For Infrequent Causal Association

Abstract
Adverse Drug Reaction (ADR) is one of the most important issues in the assessment of drug safety. In fact, many adverse drug reactions are not discovered during limited pre-marketing clinical trials instead, they are only observed after long term post-marketing surveillance of drug usage. Recently, large numbers of adverse events and the development of data mining technology have motivated the development of statistical and data mining methods for the detection of ADRs. These stand-alone methods, with no integration into knowledge discovery systems, are tedious and inconvenient for users and the processes for exploration are time-consuming. This paper proposes an interactive system platform for the detection of ADRs. By integrating an ADR data warehouse and innovative data mining techniques, the proposed system not only supports OLAP style multidimensional analysis of ADRs, but also allows the interactive discovery of associations between drugs and symptoms, called a drug-ADR association rule, which can be further developed using other factors of interest to the user, such as demographic information. The experiments indicate that interesting and valuable drug-ADR association rules can be efficiently mined.
Index Terms:adverse drug reactions, association rules, data mining algorithms, interestingness measure, Recognition Primed Decision mode
I.Introduction
Finding causal associations between two events or sets of events with relatively low frequency is very useful for various real-world applications. For example, a drug used at an appropriate dose may cause one or more adverse drug reactions (ADRs), although the probability is low. Discovering this kind of causal relationships can help us prevent or correct negative outcomes caused by its antecedents. However, mining these relationships is challenging due to the difficulty of capturing causality among events. In this paper, we try to employ a knowledge-based approach to capture the degree of causality of an event pair within each sequence we are going to match the data which was previously referred or suggested for treatment. . We then develop an interestingness measure that incorporates the causalities across all the sequences in a database.
ADRs represent a serious world-wide problem. They can complicate a patient’s medical condition or contribute to increased morbidity, even death. Studies have shown that ADRs contribute to about 5 percent of all hospital admissions.Even though premarketing clinical trials are required for all new drugs before they are approved for marketing, these trials are necessarily limited in sample-size and duration, and thus are not capable of detecting rare ADRs. Drug safety depends heavily on post marketing surveillance that is, the monitoring of impacts of medicines once they have been made available to consumers. In the US, current post marketing surveillance methods primarily rely on the FDA’s spontaneous reporting system Med Watch. Because ADR reports are filed at the discretion of the users of the system, there is gross underreporting. Systematic methods for the detection of suspected safety problems from spontaneous reports have been studied and practically implemented. For example, the FDA currently adopts a data mining algorithm called Multi-item Gamma Poisson Shrinker for detecting potential signals from its spontaneous reports. Another important signal detection strategy is known as the Bayesian Confidence Propagation Neural Network that has been used by the Uppsala Monitoring Center in routine pharmacovigilance with its World Health Organization database. Various other methods such as proportional reporting ratios empirical Bayes screening, and reporting odds ratios have been used in the spontaneous reporting centers of other nations (e.g., England and Australian). These methods have shown better performance than traditional methods. However, the performance of these techniques could be highly situation dependent due to the weaknesses and potential biases inherent in spontaneous reporting. As electronic patient records become more and more easily accessible in various health organizations such as hospitals, medical centers, and insurance companies, they provide a new source of information that has great potential to generate ADR signals much earlier. Note that each patient case can be considered as an event sequence where various events such as drug prescription, occurrence of a symptom and lab test occur at different times. In the literature, there exist a couple of studies that attempted to find the associations between drugs and potential ADRs by mining their temporal relationships. That is, they tried to mine temporal association rules (represented as → 𝑦 )) where Y occurs after X within a time window of length T. These studies obtained promising results based on administrative health data. However, temporal association was the only parameter used for linking a symptom with a drug within each patient case in their work. Temporal association assumes that cause precedes effect. Other parameters such as dechallenge and rechallenge can also give direct or indirect cues of the potential causal association of a drug-symptom pair. Dechallenge is defined as the relationship between withdrawal of the drug and abatement of the adverse effect. Rechallenge describes the relationship between reintroduction of the drug followed by recurrence of the adverse event. In addition, their approaches suffer from the sharp boundary problem. On the one hand, the symptom events near the time boundaries are either ignored or overemphasized. On the other hand, two symptom events contribute equally to the interestingness measure as long as they occur within the hazard period T. That is, the length of the time duration between exposure to the drug and occurrence of the symptom has no effect on the interestingness measure. This is not true in reality because if an ADR symptom occurs within a shorter period, it is usually more likely to be caused by the drug. To more effectively mine infrequent causal associations, it is necessary to develop a new data mining framework. This paper is a substantial extension of our previous Work where an interestingness measure called causal-leverage was developed on the basis of a computational fuzzy recognition-primed decision (RPD) model.