Idiosyncratic drug-induced liver injury (DILI) is traditionally thought not to be dose-related. However, it has been pointed out that most medicines that were withdrawn from marketing or received a black-box warning because of hepatotoxicity were prescribed at daily doses greater than 50 mg/day. To examine the relationship between daily dose of medications and idiosyncratic DILI, we conducted a study with two aims. First, using two pharmaceutical databases, we examined the relationship between daily dose of commonly prescribed medicines in the United States and reported frequency of their selected hepatic adverse events. Second, we examined serious DILI cases reported to the Swedish Adverse Drug Reactions Advisory Committee for any signals supporting the relationship between daily dose and idiosyncratic DILI. Medications were categorized into <10 mg/day, 11-49 mg/day, and >50 mg/day groups. Among US prescription medicines, a statistically significant relationship was observed between daily dose of oral medicines and reports of liver failure (P ‫؍‬ 0.009), liver transplantation (P < 0.001), and death caused by DILI (P ‫؍‬ 0.004) but not alanine aminotransferase (ALT) > 3 ؋ upper limit of normal (P ‫؍‬ 0.10) or jaundice (P ‫؍‬ 0.16). Of 598 eligible Swedish DILI cases, 9% belonged to the <10 mg/day group, 14.2% to the 11-49 mg/day group, and 77% of cases were caused by medications given at dose >50 mg/day. A statistically significant relationship was noted between daily dose and poor outcome (death or liver transplantation) of Swedish DILI cases (2%, 9.4%, and 13.2% in <10, 11-49, and >50 mg/day groups, respectively, P ‫؍‬ 0.03). Conclusion: These data suggest a relationship between daily doses of oral prescription medications and idiosyncratic DILI. More studies are needed to validate these observations and to explore their implications.

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Aims/hypothesis The aim of this study was to reduce the frequency of diabetic eye-screening visits, while maintaining safety, by using information technology and individualised risk assessment to determine screening intervals. Methods A mathematical algorithm was created based on epidemiological data on risk factors for diabetic retinopathy.Through a website, www.risk.is, the algorithm receives clinical data, including type and duration of diabetes, HbA 1c or mean blood glucose, blood pressure and the presence and grade of retinopathy. These data are used to calculate risk for sight-threatening retinopathy for each individual's worse eye over time. A risk margin is defined and the algorithm recommends the screening interval for each patient with standardised risk of developing sightthreatening retinopathy (STR) within the screening interval. We set the risk margin so that the same number of patients develop STR within the screening interval with either fixed annual screening or our individualised screening system. The database for diabetic retinopathy at the

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ObjectiveTo validate a mathematical algorithm that calculates risk of diabetic retinopathy progression in a diabetic population with UK staging (R0–3; M1) of diabetic retinopathy. To establish the utility of the algorithm to reduce screening frequency in this cohort, while maintaining safety standards.Research design and methodsThe cohort of 9690 diabetic individuals in England, followed for 2 years. The algorithms calculated individual risk for development of preproliferative retinopathy (R2), active proliferative retinopathy (R3A) and diabetic maculopathy (M1) based on clinical data. Screening intervals were determined such that the increase in risk of developing certain stages of retinopathy between screenings was the same for all patients and identical to mean risk in fixed annual screening. Receiver operating characteristic curves were drawn and area under the curve calculated to estimate the prediction capability.ResultsThe algorithm predicts the occurrence of the given diabetic retinopathy stages with area under the curve =80% for patients with type II diabetes (CI 0.78 to 0.81). Of the cohort 64% is at less than 5% risk of progression to R2, R3A or M1 within 2 years. By applying a 2 year ceiling to the screening interval, patients with type II diabetes are screened on average every 20 months, which is a 40% reduction in frequency compared with annual screening.ConclusionsThe algorithm reliably identifies patients at high risk of developing advanced stages of diabetic retinopathy, including preproliferative R2, active proliferative R3A and maculopathy M1. Majority of patients have less than 5% risk of progression between stages within a year and a small high-risk group is identified. Screening visit frequency and presumably costs in a diabetic retinopathy screening system can be reduced by 40% by using a 2 year ceiling. Individualised risk assessment with 2 year ceiling on screening intervals may be a pragmatic next step in diabetic retinopathy screening in UK, in that safety is maximised and cost reduced by about 40%.