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Register a new userSignalling Paediatric Side Effects using an Ensemble of Simple Study Designs
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Added by
Uwe Aickelin
Publication date
2014
fields
Informatics Engineering
and research's language is
English
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Background: Children are frequently prescribed medication off-label, meaning there has not been sufficient testing of the medication to determine its safety or effectiveness. The main reason this safety knowledge is lacking is due to ethical restrictions that prevent children from being included in the majority of clinical trials. Objective: The objective of this paper is to investigate whether an ensemble of simple study designs can be implemented to signal acutely occurring side effects effectively within the paediatric population by using historical longitudinal data. The majority of pharmacovigilance techniques are unsupervised, but this research presents a supervised framework. Methods: Multiple measures of association are calculated for each drug and medical event pair and these are used as features that are fed into a classiffier to determine the likelihood of the drug and medical event pair corresponding to an adverse drug reaction. The classiffier is trained using known adverse drug reactions or known non-adverse drug reaction relationships. Results: The novel ensemble framework obtained a false positive rate of 0:149, a sensitivity of 0:547 and a specificity of 0:851 when implemented on a reference set of drug and medical event pairs. The novel framework consistently outperformed each individual simple study design. Conclusion: This research shows that it is possible to exploit the mechanism of causality and presents a framework for signalling adverse drug reactions effectively.
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The electronic healthcare databases are starting to become more readily available and are thought to have excellent potential for generating adverse drug reaction signals. The Health Improvement Network (THIN) database is an electronic healthcare database containing medical information on over 11 million patients that has excellent potential for detecting ADRs. In this paper we apply four existing electronic healthcare database signal detecting algorithms (MUTARA, HUNT, Temporal Pattern Discovery and modified ROR) on the THIN database for a selection of drugs from six chosen drug families. This is the first comparison of ADR signalling algorithms that includes MUTARA and HUNT and enabled us to set a benchmark for the adverse drug reaction signalling ability of the THIN database. The drugs were selectively chosen to enable a comparison with previous work and for variety. It was found that no algorithm was generally superior and the algorithms natural thresholds act at variable stringencies. Furthermore, none of the algorithms perform well at detecting rare ADRs.
In previous work, a novel supervised framework implementing a binary classifier was presented that obtained excellent results for side effect discovery. Interestingly, unique side effects were identified when different binary classifiers were used within the framework, prompting the investigation of applying a multiple classifier system. In this paper we investigate tuning a side effect multiple classifying system using genetic algorithms. The results of this research show that the novel framework implementing a multiple classifying system trained using genetic algorithms can obtain a higher partial area under the receiver operating characteristic curve than implementing a single classifier. Furthermore, the framework is able to detect side effects efficiently and obtains a low false positive rate.
Multi-objective optimization is key to solving many Engineering Design problems, where design parameters are optimized for several performance indicators. However, optimization results are highly dependent on how the designs are parameterized. Researchers have shown that deep generative models can learn compact design representations, providing a new way of parameterizing designs to achieve faster convergence and improved optimization performance. Despite their success in capturing complex distributions, existing generative models face three challenges when used for design problems: 1) generated designs have limited design space coverage, 2) the generator ignores design performance, and 3)~the new parameterization is unable to represent designs beyond training data. To address these challenges, we propose MO-PaDGAN, which adds a Determinantal Point Processes based loss function to the generative adversarial network to simultaneously model diversity and (multi-variate) performance. MO-PaDGAN can thus improve the performances and coverage of generated designs, and even generate designs with performances exceeding those from training data. When using MO-PaDGAN as a new parameterization in multi-objective optimization, we can discover much better Pareto fronts even though the training data do not cover those Pareto fronts. In a real-world multi-objective airfoil design example, we demonstrate that MO-PaDGAN achieves, on average, an over 180% improvement in the hypervolume indicator when compared to the vanilla GAN or other state-of-the-art parameterization methods.
Designing reward functions for reinforcement learning is difficult: besides specifying which behavior is rewarded for a task, the reward also has to discourage undesired outcomes. Misspecified reward functions can lead to unintended negative side effects, and overall unsafe behavior. To overcome this problem, recent work proposed to augment the specified reward function with an impact regularizer that discourages behavior that has a big impact on the environment. Although initial results with impact regularizers seem promising in mitigating some types of side effects, important challenges remain. In this paper, we examine the main current challenges of impact regularizers and relate them to fundamental design decisions. We discuss in detail which challenges recent approaches address and which remain unsolved. Finally, we explore promising directions to overcome the unsolved challenges in preventing negative side effects with impact regularizers.
Drugs are frequently prescribed to patients with the aim of improving each patients medical state, but an unfortunate consequence of most prescription drugs is the occurrence of undesirable side effects. Side effects that occur in more than one in a thousand patients are likely to be signalled efficiently by current drug surveillance methods, however, these same methods may take decades before generating signals for rarer side effects, risking medical morbidity or mortality in patients prescribed the drug while the rare side effect is undiscovered. In this paper we propose a novel computational meta-analysis framework for signalling rare side effects that integrates existing methods, knowledge from the web, metric learning and semi-supervised clustering. The novel framework was able to signal many known rare and serious side effects for the selection of drugs investigated, such as tendon rupture when prescribed Ciprofloxacin or Levofloxacin, renal failure with Naproxen and depression associated with Rimonabant. Furthermore, for the majority of the drug investigated it generated signals for rare side effects at a more stringent signalling threshold than existing methods and shows the potential to become a fundamental part of post marketing surveillance to detect rare side effects.
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