More rigorous diagnostic aids might therefore be helpful in defining a likelihood. In particular, standardized decision algorithms such as the adr Probability Scale (aps), a questionnaire with a pre-set weighted scoring system for specific case features, have increased interrater reliability and identified factors that are important for diagnosing adrs. A midrange score of +4 was obtained for this case (total possible score -4 to +13).

A further advancement developed by members of our group used a method of probabilistic differential diagnosis that has a better discriminatory ability compared with aps. The Bayesian Adverse Reaction Diagnostic Instrument (bardi)treats the differential diagnosis of adverse events as a special case of conditional probability evaluation in which the goal is to calculate the probability in favour of the drug in question versus alternate possible causes being responsible. This method combines epidemiological and clinical trial data regarding the adverse event (expressed as a prior odds) and details specific to the particular case (each expressed as a likelihood ratio). The information is entered onto a computerized spreadsheet (bardi-Q&A) and the output is the posterior odds favouring drug causation, calculated as the product of the prior odds and the likelihood ratios (Figure 3). bardi has been applied successfully to a number of serious adverse events. ventolin inhaler

**Figure 3)** *Definitions for calculations used in the Bayesi an Adverse Reaction Diagnostic Instrument (BARDI). LR Likelihood ratio*

The Bayesian analysis of this case is outlined as follows. Prior odds: The drug associated risk is 6/ 106/ year based on six reports of aplastic anemia over about 10 years and about 100,000 personstreated per year. The nondrug associated risk is 2.2/ 106/ year based on a study of the incidence of aplastic anemia. The prior odds is a ratio of these risks and equals 2.73.

Case pertinent information-Likelihood ratios (LRs):History – If there had been symptoms or signs suggestive of a particular etiology, either drug or nondrug, the probability would be changed. In the absence of specific information, this lr remains 1. Timing – Based on a time distribution of reported cases of severe leukopenia associated with ticlopidine, most (52%) cases of aplastic anemia would be expected to occur between 31 and 40 days (as was observed in this case) with other events falling in a roughly bell-shaped distribution around this interval. In contrast, cases not attributable to the drug would be seen with equal frequency throughout this horizon of 70 days, translating to 17% per 10 day period. The lr is 0.52/ 0.17 and equals 3.71. Characteristics, dechallenge, rechallenge -No information was available for these categories and therefore their lrs each equal 1.