Importance of Improving Prescribing using Fuzzy Pharmacology Expert System, A Theory Perspective

Taghi Karimi
Department of Mathematics, Payame Noor University, P. O. Box 19395-4697, Tehran, Iran.

International Journal of Advances in Science and Technology, Vol. 4, No.2, 2012

Abstract
Predicting outcomes of pharmacotherapy is difficult because of the many sources of pharmacokinetic and pharmacodynamic variation. Several of these sources of variation have been recognized for many years: for example, age, gender, weight, disease state, genetic polymorphisms and concomitant medications. In general, the pharmacological system is described in mathematical terms, where variables are associated with the outcome of interest in terms of equations with identified parameters (e.g. Rate constants). Parameter values are estimated with statistical error values attached to describe variability. Approaches that are conceptually different from this traditional approach have evolved in the field of engineering when confronted with very complex systems. We propose the approach of fuzzy logic modeling might be particularly suitable for pharmacological problems. In this paper we mentioned the limitation of usual expert system for prescription and drug interaction checker. We proposed the architecture and theory based fundamental of fuzzy expert system for improving the performance of prescription.

Keywords: Fuzzy logic, Fuzzy expert system, Drug interaction, Pharmacy system, Pharmacy information system (PIS). 1. Introduction
The concurrent use of multiple drugs is often attended with drug-drug interactions, which represent an important category of adverse reactions to drugs [1-3]. Since information on drug interactions is huge in volume, scattered around in the literature, and still increasing, it is hardly possible to check potentially dangerous drug combinations completely by manual method, particularly when a patient is administered the multitude of drugs. As an aid for the medical practitioners, some computerized drug information systems provide the services of drug-drug interaction checking [4-9]. Adverse drugs reaction (ADR) and harmful effects of pharmaceutical excipients imply severe incidences, due to incompatibilities of the drug with the medical history. The rate of ADR appearance is extremely high in worldwide hospitals [10]. Hence, it represents an important clinical issue. Some studies have shown an ADR incidence about 6.7% of serious cases and 0.32% of deaths [11], over the total cases attended in worldwide hospitals. In Iranian hospitals the ADR ratio is so high. An example of ADR consequences are, according to the study carried out by the Shahid Beheshti University Hospital (Iran), admission in 80% of cases, with a medium bed stay of eight days, a cost of $847m and an overall fatality of 0.15%. Most of these consequences can be avoided with a review of drug interaction and allergies with some of the excipients. For this reason, we propose a theoretical view of a fuzzy based expert system for prescription checking and drug-drug interaction detector to detect ADRs and drug interactions. Our solution can comprise a personal system to check the drug suitability using a wearable or mobile device, such as cellular phones, PDAs or laptops. The mobile device identifies the drug by means of NFC (Near Field Communication) or barcode. The compatibility of the drug with the patient profile is checked with the Pharmaceutical Information System (PIS), to detect whether the product is suitable according to the allergy profile and medical history (EHR). The Pharmaceutical Information System is composed of a database with all the drugs description, active ingredients, side effects etc., an ontology to define the patient's profile, including drugs concepts, and formally a rule-based system to detect allergies and

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International Journal of Advances in Science and Technology, Vol. 4, No.2, 2012 adverse drug reactions. Some initial approaches to a Pharmaceutical Information System can be found in [13-15]. Concretely, a real deployment of the system is reached in [17], in Japan and Spain, respectively.

2. Fuzzy pharmacology expert system

Expert systems were initially designed to capture the human reasoning thought process. In order to do this, a number of approaches were considered for possible knowledge representation structures, including production rules, frames, and neural nets [20]. All of these approaches have succeeded in some applications, and it appears that the application itself dictates the most suitable approach. Many such examples exist in the medical field [19]. However, all suffer from the same shortcoming. The part of reasoning at which humans are very good - dealing with imprecise information - is lacking from these approaches. Some systems have attempted to use ad hoc procedures such as certainty factors to incorporate the flavor of this type of reasoning [17], but most do not delve deeply enough into the sources of uncertainty in the system. Fortunately, a number of approaches for handling the troubling problem of uncertainty can be found in the field of fuzzy logic, an area which has also been developing rapidly in recent years [16]. Some of the theoretical work has begun to be applied to expert systems [4]. A fuzzy expert system is simply an expert system that uses a collection of fuzzy membership functions and rules, instead of Boolean logic, to reason about data. The rules in a fuzzy expert system are usually of a form similar to the following: If A is low and B is high then X = medium where A and B are input variables, X is an output variable. Here low, high, and medium are fuzzy sets dened on A, B, and X respectively. The antecedent (the rules premise) describes to what degree the rule applies, while the rules consequent assigns a membership function to each of one or more output variables. Let X be a space of the objects and x be a generic element of X. A classical element set A, AX is defined as a collection of elements or objects xX, such as x can be either belong or not belong to the set A. A fuzzy set A in X is dened as a set of ordered pairs
A {( x, A ( x)) | x X )}

(1)

where A is called the membership function (MF) for the fuzzy set A. The MF maps each element of X to a membership grade (or membership value) between zero and one. Obviously (1) is a simple extension of the denition of a classical set in which the characteristic function is permitted to have any values between zero and one.
FUZZY PHARMACOLOGY CONCEPT

Fuzzy pharmacology is a term coined to represent the application of fuzzy logic and fuzzy set theory to pharmacological problems such as prescription checker or drug interaction detector. As we mentioned above, Fuzzy logic is the science of reasoning, thinking and inference that recognizes and uses the real world phenomenon that everything is a matter of degree. It is an extension of binary logic that is able to deal with complex systems because it does not require crisp definitions and distinctions for the system components. In pharmacology, fuzzy modeling can been used for the prescribing checker, and work has begun evaluating its use in other pharmacokinetic and pharmacodynamic applications. Medicine is often described as both science and art, the blend of which makes viewing medical problems in a fuzzy manner intriguing. Therefore, it is not surprising that the concepts of fuzziness and fuzzy systems have been applied in medicine in many diverse ways.

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3. Sources of imprecision in pharmacology

Imprecision in knowledge based systems can be divided into two categories: imprecision in the knowledge base, imprecision in the data for the case at hand, and imprecision in the interpretation of the results. Each will be analyzed in turn.
IMPRECISION IN THE KNOWLEDGE BASE

The knowledge base must contain two types of information: factual information, and a method for reasoning with the factual information. As an example of factual information in a medical system, one may have a statement of the type: If blood sugar > 200, then patient is diabetic. However, this factual statement should more accurately read. If blood sugar is high then patient may be diabetic. In other words, 200 is in fact an arbitrary figure, and even if the blood sugar is very high, the conclusion of presence of diabetes is not certain. The problem is that the first statement is easily handled in production rule format, while the second is not. Thus we see that the statement is not actually factual information but should more accurately be termed a guideline. The situation is then complicated by the problem of combining a number of such guidelines in a more complex reasoning situation. For example, If blood pressure is low and skin is cold and clammy or skin is grey and cyanotic then patient should be admitted to the hospital. Thus a combination of conjunctions (AND's) and disjunctions (OR's) are present along with imprecise statements such as "blood pressure is low". In addition to conjunctions and disjunctions, a third type of logical construct appears to be present in the human reasoning process. Consider, for example, If any three of the following hold for oral glucose tolerance test: fasting plasma glucose 115mg % 1 hr plasma glucose 185mg % 2 hr plasma glucose 140 mg % 3 hr plasma glucose 115mg % then patient has diabetes. Here, a new logical construct occurs in the form of requiring a certain number in a list to hold. In addition, another problem is raised by this example. What if the fasting glucose at one hour is 184, at 2 hr. is 150, and at 3 hr, is 114? Should this patient then be diagnosed as diabetic? In other word, how precisely should these cut-off values be interpreted? A final complication arises in the possibility that not all four of these guidelines carry equal weight. For example, the first test may in fact be more important than the other three.
IMPRECISION IN THE DATA

Consider the recording of medical data. Some of it appears to be precise in nature. For instance, a pulse rate may be exactly 77 beats/minute. However, if the pulse is re-measured in 5 minutes, it may be precisely 82 beats/minute. Thus although the reading is precise at any given point in time, it is subject to change within a very short time period. It thus becomes dangerous to use the pulse rate as an absolute value in a rule antecedent. The same is true for blood pressure and other vital signs which fluctuate with time. For tenthly, those readings generally only fluctuate within a narrow range of values in the short term. Other medical data causes different problems. This is particularly true in the subjective recording of a symptom, such as "Is the patient sweating?" A yes/no answer to this question is probably insufficient, as the degree of the severity of the sweating may indeed by important. Yet another category of medical data is of the interpretative type, such as a radiologist's determination of whether an x-ray is normal or abnormal, or a cardiologist's determination of whether an electrocardiogram shows irregularities.

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IMPRECISION IN INTERPRETATION OF RESULTS

Assuming all of the above difficulties have been overcome, the final difficulty arises in the interpretation of results. Results from a computer are usually interpreted as absolutes. Yet a diagnosis of diabetes disease by an expert system usually is only made with a certain degree of confidence. It is more important to make this point clear in a decision reached by a computer, as the uncertainty seems to be more implicitly assumed in human reasoning.

4. Method
HANDLING OF PHARMACOLOGY UNCERTAINTY Fuzzy expert system modeling can be pursued using the following steps. Select relevant input and output variables. Determine the number of linguistic terms associated with each input/output variable (can called from EHR). Also, choose the appropriate family of membership functions, fuzzy operators, reasoning mechanism, and so on. Choose a specic type of fuzzy inference system (for example, Mamdani, TakagiSugeno etc.). In most cases, the inference of the fuzzy rules is carried out using the min and max operators for fuzzy intersection and union. Design a collection of fuzzy if-then rules (knowledge base). To formulate the initial rule base, the input space is divided into multidimensional partitions and then actions are assigned to each of the partitions. In Our proposed method, the partitioning is achieved using one dimensional membership functions using fuzzy if-then rules as illustrated in Figure 1. The consequent parts of the rule represent the actions associated with each partition. It is evident that the MFs and the number of rules are tightly related to the partitioning.

Figure 1. Example showing how the two-dimensional spaces are partitioned using three trapezoidal membership functions per input dimension.

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FUZZY PHARMACOKINETIC MODELING

Fuzzy logic pharmacokinetic modeling has been proposed and evaluated in only a few applications. We conducted preliminary work where five input variables were modeled (age, weight, serum creatinine, lithium dose and time since last dose) to predict the drug dosage (range 0.201.24mmol l1). The average magnitude of the error in the predictions was 0.13 mmol l1 (CI, 0.09,0.16), calculated as the root mean of the squared prediction errors with a bias of 0.03 mmol l1 (CI, 0.01,0.06), calculated as the mean of the prediction errors. This study indicated that the use of fuzzy logic for pharmacokinetic modeling is feasible. This feasibility was also demonstrated in our analogous experiments conducted using alprazolam pharmacokinetic data [11]. Explorations should continue into the benefits of fuzzy logic modeling in clinical pharmacokinetics, particularly to predict drug interaction to compare its predictive performance to other pharmacokinetic modeling techniques to ascertain the strengths and weakness of each. Perhaps a combination of approaches will prove to be optimal. For example, although not using a pharmacological application, Lee and colleagues [18] have suggested a fuzzy logic approach to modify algebraic enzyme kinetic equations in order to incorporate qualitative knowledge. This could also potentially be applied to drugreceptor interaction modeling. Likewise, explorations into using self-adapting fuzzy rule bases for feedback control to individualize dosing regimens or in combination with Bayesian feedback methods are yet to be done. Fuzzy approaches might be useful in preclinical pharmacokinetic modeling. In [20] the authors described a fuzzy simulation approach to model variability and uncertainty when there is vague information available about model parameters. In this case the model parameters are represented as fuzzy sets rather than mean values to allow modeling at very early stages of toxicokineticpharmacokinetic evaluation.
FUZZY PHARMACODYNAMIC MODELING

In pharmacodynamic modeling the effect of the drug is commonly related to the concentration of the drug (i.e. doseresponse evaluations). Fuzzy logic pharmacodynamic modeling has been evaluated, for example, in a study analyzing the relationship between hemodynamic variables, auditory evoked potentials (AEPs) and the inspired fraction of isoflurane [19]. The objective of this study was to specifically look at the relationships between clinical variables and doseresponse. For example, using data recorded during the surgeries of nine female patients undergoing hysterectomy, a model was designed to predict the amount of anesthetic required by the patient based on clinical variables such as heart rate and AEPs. The model predicted the anesthetic dose with a mean error of 12%. In another example, a combined fuzzy linear-regression method has been proposed to assess the doseresponse relationship between nitrate exposure (from food and water) and cancer risk [20]. Fuzzy pharmacodynamic modeling can be used to predict who will benefit most from a drug. In a preliminary study, clinical trial data was used to predict response to alcohol dependence treatment. A rule base was developed that related citalopram (40 mg day1, n = 34) response (percent decrease in alcohol intake) with depression, anxiety, alcohol dependence severity, age and baseline alcohol intake (root mean squared error = 2.6%, mean error = 0.6%) [16]. Other preliminary work includes using a fuzzy model to predict appropriate antibiotic treatment (including combinations of antibiotics) in patients with pneumonia [18] and for designing a measles vaccination strategy in Brazil [21].

5. Discussion

Evaluating the use of fuzzy sets and fuzzy logic in pharmacology has barely begun. To date, such evaluation has been used primarily to model the actions of drugs and thereby control the delivery of drugs that are infused, exhibit rapid and directly measurable pharmacological effects and have short durations of action. The challenge is to model pharmacokinetic and pharmacodynamic systems, for example, where the drug response is delayed or subjective in nature or measured by indirect clinical effects and in situations where several clinical features or environmental factors influence the outcome. Fuzzy logic approaches appear promising in preclinical applications and might be useful in drug discovery and design. Applications analogous to those in other areas of medicine could be further explored, including fuzzy logic decision-making algorithms (e.g. pharmacoeconomics) and fuzzy logic analysis for detection of drug interaction and it's improve the quality of prescription.

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6. References
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Authors Profile
Dr. Taghi Karimi received the B. Sc degree in mathematics from the Payame Noor University of Mashhad, Iran in 1996 and the Ph. D degree in mathematics from Azad University of Mashhad in 2006. He has published over 20 peer-reviewed

journal papers and contributed to more than 7 conference papers and presentations. His research activities include group theory, number theory, algebraic topology and game theory.

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