G. Niklas Norén

Suspected Adverse Drug Reactions Reported For Children Worldwide An Exploratory Study Using VigiBase

AbstractBackground: As a first step towards implementing routine screening of safety issues specifically related to children at the Uppsala Monitoring Centre, this study was performed to explore reporting patterns of adverse reactions in children. Objective: The first aim of this study was to characterize and contrast child reports against adult reports in an overall drug and adverse reaction review. The second aim was to highlight increases in reporting of specific adverse reactions during recent years subdivided by age group. Study Design: This was an exploratory study of internationally compiled individual case safety reports (ICSRs). Setting: Reports were extracted from the WHO global ICSR database, VigiBase, up until 5 February 2010. The reports in VigiBase originate from 97 countries and the likelihood that a medicine caused the adverse effect may vary from case to case. Suspected duplicate and vaccine reports were excluded from the analysis, as were reports with age not specified. The Medical Dictionary for Regulatory Activities (MedDRA®) and the WHO Anatomical Therapeutic Chemical (ATC) classification were used to group adverse reactions and drugs. Patients: In the general review, reports from 1968 to 5 February 2010 were divided into child (aged 0–17 years) and adult (≥18 years) age groups. To highlight increases in reporting rates of specific adverse reactions during recent years, reports from 2005 to February 2010 were compared with reports from 1995 to 1999. The ten adverse reactions with the greatest difference in the proportion of reports between the two time periods were reviewed. In the latter analysis, the reports were subdivided into age groups: neonates ≤27 days; infants 28 days–23 months; children 2–11 years; and adolescents 12–17 years. Results: A total of 3 472 183 reports were included in the study, of which 7.7% (268 145) were reports for children (0–17 years). Fifty-three percent of the child reports were for males, whilst 39% of reports in the adult group were for males. The proportion of reports involving children among Asian reports was 14% and was 15% among reports from Africa and Latin America, including the Caribbean. Among reports from North America, Oceania and Europe, 7% of the reports involved children. For the ATC drug classification groups, the largest difference in percentage units between the child and adult groups was seen for the anti-infective (33 vs 15%), respiratory (11 vs 5%) and dermatological (12 vs 7%) drug groups. Skin reactions were most commonly reported for the children; these were recorded in 35% of all reports for children and 23% of all reports for adults. Medication error-related terms in the younger age groups were reported with an increased frequency during recent years. This was particularly noticeable for the infants aged 28 days–23 months, recorded with accidental overdose and drug toxicity. Reactions reported in suspected connection to medicines used for attention-deficit hyperactivity disorders (ADHD) completely dominated the 2-to 11-year age group and were also common for the adolescents. This study presents variations in the reporting pattern in different age groups in VigiBase which, in some cases, could be due to susceptibilities to specific drug-related problems in certain age groups. Other likely explanations might be common drug usage and childhood diseases in these age groups. Conclusions: Reports in VigiBase received internationally for more than 40 years reflect real concerns for children taking medicines. The study highlights adverse reactions with an increased reporting during recent years, particularly those connected to the introduction of ADHD medicines in the child population. To enhance patient safety, medication errors indicating administration and dosing difficulties of drugs, especially in the younger age groups, require further attention.

A statistical methodology for drug-drug interaction surveillance

Interaction between drug substances may yield excessive risk of adverse drug reactions (ADRs) when two drugs are taken in combination. Collections of individual case safety reports (ICSRs) related to suspected ADR incidents in clinical practice have proven to be very useful in post-marketing surveillance for pairwise drug--ADR associations, but have yet to reach their full potential for drug-drug interaction surveillance. In this paper, we implement and evaluate a shrinkage observed-to-expected ratio for exploratory analysis of suspected drug-drug interaction in ICSR data, based on comparison with an additive risk model. We argue that the limited success of previously proposed methods for drug-drug interaction detection based on ICSR data may be due to an underlying assumption that the absence of interaction is equivalent to having multiplicative risk factors. We provide empirical examples of established drug-drug interaction highlighted with our proposed approach that go undetected with logistic regression. A database wide screen for suspected drug-drug interaction in the entire WHO database is carried out to demonstrate the feasibility of the proposed approach. As always in the analysis of ICSRs, the clinical validity of hypotheses raised with the proposed method must be further reviewed and evaluated by subject matter experts.

Duplicate detection in adverse drug reaction surveillance

The WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden, maintains and analyses the world’s largest database of reports on suspected adverse drug reaction (ADR) incidents that occur after drugs are on the market. The presence of duplicate case reports is an important data quality problem and their detection remains a formidable challenge, especially in the WHO drug safety database where reports are anonymised before submission. In this paper, we propose a duplicate detection method based on the hit-miss model for statistical record linkage described by Copas and Hilton, which handles the limited amount of training data well and is well suited for the available data (categorical and numerical rather than free text). We propose two extensions of the standard hit-miss model: a hit-miss mixture model for errors in numerical record fields and a new method to handle correlated record fields, and we demonstrate the effectiveness both at identifying the most likely duplicate for a given case report (94.7% accuracy) and at discriminating true duplicates from random matches (63% recall with 71% precision). The proposed method allows for more efficient data cleaning in post-marketing drug safety data sets, and perhaps other knowledge discovery applications as well.

Observational Health Data Sciences and Informatics (OHDSI): Opportunities for Observational Researchers.

The vision of creating accessible, reliable clinical evidence by accessing the clincial experience of hundreds of millions of patients across the globe is a reality. Observational Health Data Sciences and Informatics (OHDSI) has built on learnings from the Observational Medical Outcomes Partnership to turn methods research and insights into a suite of applications and exploration tools that move the field closer to the ultimate goal of generating evidence about all aspects of healthcare to serve the needs of patients, clinicians and all other decision-makers around the world.

Shrinkage observed-to-expected ratios for robust and transparent large-scale pattern discovery

Large observational data sets are a great asset to better understand the effects of medicines in clinical practice and, ultimately, improve patient care. For an empirical pattern in observational data to be of practical relevance, it should represent a substantial deviation from the null model. For the purpose of identifying such deviations, statistical significance tests are inadequate, as they do not on their own distinguish the magnitude of an effect from its data support. The observed-to-expected (OE) ratio on the other hand directly measures strength of association and is an intuitive basis to identify a range of patterns related to event rates, including pairwise associations, higher order interactions and temporal associations between events over time. It is sensitive to random fluctuations for rare events with low expected counts but statistical shrinkage can protect against spurious associations. Shrinkage OE ratios provide a simple but powerful framework for large-scale pattern discovery. In this article, we outline a range of patterns that are naturally viewed in terms of OE ratios and propose a straightforward and effective statistical shrinkage transformation that can be applied to any such ratio. The proposed approach retains emphasis on the practical relevance and transparency of highlighted patterns, while protecting against spurious associations.

Temporal pattern discovery for trends and transient effects: its application to patient records

We introduce a novel pattern discovery methodology for event history data focusing explicitly on the detailed temporal relationship between pairs of events. At the core is a graphical statistical approach to summarising and visualising event history data, which contrasts the observed to the expected incidence of the event of interest before and after an index event. Thus, pattern discovery is not restricted to a specific time window of interest, but encompasses extended parts of the underlying event histories. In order to effectively screen large collections of event history data for interesting temporal relationships, we introduce a new measure of temporal association. The proposed measure contrasts the observed-to-expected ratio in a time period of interest to that in a pre-defined control period. An important feature of both the observed-to-expected graph itself and the measure of association, is a statistical shrinkage towards the null hypothesis of no association. This provides protection against spurious associations and is an extension of the statistical shrinkage successfully applied to large-scale screening for associations between events in cross-sectional data, such as large collections of adverse drug reaction reports. We demonstrate the usefulness of the proposed pattern discovery methodology by a set of examples from a collection of over two million patient records in the United Kingdom. The identified patterns include temporal relationships between drug prescription and medical events suggestive of persistent or transient risks of adverse events, as well as temporal relationships between prescriptions of different drugs.

Impact of Stratification on Adverse Drug Reaction Surveillance

AbstractBackground and objectives: Automated screening for excessive adverse drug reaction (ADR) reporting rates has proven useful as a tool to direct clinical review in large-scale drug safety signal detection. Some measures of disproportionality can be adjusted to eliminate any undue influence on the ADR reporting rate of covariates, such as patient age or country of origin, by using a weighted average of stratum-specific measures of disproportionality. Arguments have been made in favour of routine adjustment for a set of common potential confounders using stratification. The aim of this paper is to investigate the impact of using adjusted observed-to-expected ratios, as implemented for the Empirical Bayes Geometric Mean (EBGM) and the information component (IC) measures of disproportionality, for first-pass analysis of the WHO database. Methods: A simulation study was carried out to investigate the impact of simultaneous adjustment for several potential confounders based on stratification. Comparison between crude and adjusted observed-to-expected ratios were made based on random allocation of reports to a set of strata with a realistic distribution of stratum sizes. In a separate study, differences between the crude IC value and IC values adjusted for (combinations of) patient sex, age group, reporting quarter and country of origin, with respect to their concordance with a literature comparison were analysed. Comparison was made to the impact on signal detection performance of a triage criterion requiring reports from at least two countries before a drug-ADR pair was highlighted for clinical review. Results: The simulation study demonstrated a clear tendency of the adjusted observed-to-expected ratio to spurious (and considerable) underestimation relative to the crude one, in the presence of any very small strata in a stratified database. With carefully implemented stratification that did not yield any very small strata, this tendency could be avoided. Routine adjustment for potential confounders improved signal detection performance relative to the literature comparison, but the magnitude of the improvement was modest. The improvement from the triage criterion was more considerable. Discussion and conclusions: Our results indicate that first-pass screening based on observed-to-expected ratios adjusted with stratification may lead to missed signals in ADR surveillance, unless very small strata are avoided. In addition, the improvement in signal detection performance due to routine adjustment for a set of common confounders appears to be smaller than previously assumed. Other approaches to improving signal detection performance such as the development of refined triage criteria may be more promising areas for future research.

Bridging Islands of Information to Establish an Integrated Knowledge Base of Drugs and Health Outcomes of Interest

The entire drug safety enterprise has a need to search, retrieve, evaluate, and synthesize scientific evidence more efficiently. This discovery and synthesis process would be greatly accelerated through access to a common framework that brings all relevant information sources together within a standardized structure. This presents an opportunity to establish an open-source community effort to develop a global knowledge base, one that brings together and standardizes all available information for all drugs and all health outcomes of interest (HOIs) from all electronic sources pertinent to drug safety. To make this vision a reality, we have established a workgroup within the Observational Health Data Sciences and Informatics (OHDSI, http://ohdsi.org) collaborative. The workgroup’s mission is to develop an open-source standardized knowledge base for the effects of medical products and an efficient procedure for maintaining and expanding it. The knowledge base will make it simpler for practitioners to access, retrieve, and synthesize evidence so that they can reach a rigorous and accurate assessment of causal relationships between a given drug and HOI. Development of the knowledge base will proceed with the measureable goal of supporting an efficient and thorough evidence-based assessment of the effects of 1,000 active ingredients across 100 HOIs. This non-trivial task will result in a high-quality and generally applicable drug safety knowledge base. It will also yield a reference standard of drug–HOI pairs that will enable more advanced methodological research that empirically evaluates the performance of drug safety analysis methods.

A hit-miss model for duplicate detection in the WHO drug safety database

The WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden, maintains and analyses the worlds largest database of reports on suspected adverse drug reaction incidents that occur after drugs are introduced on the market. As in other post-marketing drug safety data sets, the presence of duplicate records is an important data quality problem and the detection of duplicates in the WHO drug safety database remains a formidable challenge, especially since the reports are anonymised before submitted to the database. However, to our knowledge no work has been published on methods for duplicate detection in post-marketing drug safety data. In this paper, we propose a method for probabilistic duplicate detection based on the hit-miss model for statistical record linkage described by Copas & Hilton. We present two new generalisations of the standard hit-miss model: a hit-miss mixture model for errors in numerical record fields and a new method to handle correlated record fields. We demonstrate the effectiveness of the hit-miss model for duplicate detection in the WHO drug safety database both at identifying the most likely duplicate for a given record (94.7% accuracy) and at discriminating duplicates from random matches (63% recall with 71% precision). The proposed method allows for more efficient data cleaning in post-marketing drug safety data sets, and perhaps other applications throughout the KDD community.

Improved statistical signal detection in pharmacovigilance by combining multiple strength-of-evidence aspects in vigiRank.

BackgroundDetection of unknown risks with marketed medicines is key to securing the optimal care of individual patients and to reducing the societal burden from adverse drug reactions. Large collections of individual case reports remain the primary source of information and require effective analytics to guide clinical assessors towards likely drug safety signals. Disproportionality analysis is based solely on aggregate numbers of reports and naively disregards report quality and content. However, these latter features are the very fundament of the ensuing clinical assessment.ObjectiveOur objective was to develop and evaluate a data-driven screening algorithm for emerging drug safety signals that accounts for report quality and content.MethodsvigiRank is a predictive model for emerging safety signals, here implemented with shrinkage logistic regression to identify predictive variables and estimate their respective contributions. The variables considered for inclusion capture different aspects of strength of evidence, including quality and clinical content of individual reports, as well as trends in time and geographic spread. A reference set of 264 positive controls (historical safety signals from 2003 to 2007) and 5,280 negative controls (pairs of drugs and adverse events not listed in the Summary of Product Characteristics of that drug in 2012) was used for model fitting and evaluation; the latter used fivefold cross-validation to protect against over-fitting. All analyses were performed on a reconstructed version of VigiBase® as of 31 December 2004, at around which time most safety signals in our reference set were emerging.ResultsThe following aspects of strength of evidence were selected for inclusion into vigiRank: the numbers of informative and recent reports, respectively; disproportional reporting; the number of reports with free-text descriptions of the case; and the geographic spread of reporting. vigiRank offered a statistically significant improvement in area under the receiver operating characteristics curve (AUC) over screening based on the Information Component (IC) and raw numbers of reports, respectively (0.775 vs. 0.736 and 0.707, cross-validated).ConclusionsAccounting for multiple aspects of strength of evidence has clear conceptual and empirical advantages over disproportionality analysis. vigiRank is a first-of-its-kind predictive model to factor in report quality and content in first-pass screening to better meet tomorrow’s post-marketing drug safety surveillance needs.