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Register a new userRefining adverse drug reaction signals by incorporating interaction variables identified using emergent pattern mining
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Added by
Uwe Aickelin
Publication date
2016
fields
Informatics Engineering
and research's language is
English
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Purpose: To develop a framework for identifying and incorporating candidate confounding interaction terms into a regularised cox regression analysis to refine adverse drug reaction signals obtained via longitudinal observational data. Methods: We considered six drug families that are commonly associated with myocardial infarction in observational healthcare data, but where the causal relationship ground truth is known (adverse drug reaction or not). We applied emergent pattern mining to find itemsets of drugs and medical events that are associated with the development of myocardial infarction. These are the candidate confounding interaction terms. We then implemented a cohort study design using regularised cox regression that incorporated and accounted for the candidate confounding interaction terms. Results The methodology was able to account for signals generated due to confounding and a cox regression with elastic net regularisation correctly ranked the drug families known to be true adverse drug reactions above those.
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Side effects of prescribed medications are a common occurrence. Electronic healthcare databases present the opportunity to identify new side effects efficiently but currently the methods are limited due to confounding (i.e. when an association between two variables is identified due to them both being associated to a third variable). In this paper we propose a proof of concept method that learns common associations and uses this knowledge to automatically refine side effect signals (i.e. exposure-outcome associations) by removing instances of the exposure-outcome associations that are caused by confounding. This leaves the signal instances that are most likely to correspond to true side effect occurrences. We then calculate a novel measure termed the confounding-adjusted risk value, a more accurate absolute risk value of a patient experiencing the outcome within 60 days of the exposure. Tentative results suggest that the method works. For the four signals (i.e. exposure-outcome associations) investigated we are able to correctly filter the majority of exposure-outcome instances that were unlikely to correspond to true side effects. The method is likely to improve when tuning the association rule mining parameters for specific health outcomes. This paper shows that it may be possible to filter signals at a patient level based on association rules learned from considering patients medical histories. However, additional work is required to develop a way to automate the tuning of the methods parameters.
Big longitudinal observational medical data potentially hold a wealth of information and have been recognised as potential sources for gaining new drug safety knowledge. Unfortunately there are many complexities and underlying issues when analysing longitudinal observational data. Due to these complexities, existing methods for large-scale detection of negative side effects using observational data all tend to have issues distinguishing between association and causality. New methods that can better discriminate causal and non-causal relationships need to be developed to fully utilise the data. In this paper we propose using a set of causality considerations developed by the epidemiologist Bradford Hill as a basis for engineering features that enable the application of supervised learning for the problem of detecting negative side effects. The Bradford Hill considerations look at various perspectives of a drug and outcome relationship to determine whether it shows causal traits. We taught a classifier to find patterns within these perspectives and it learned to discriminate between association and causality. The novelty of this research is the combination of supervised learning and Bradford Hills causality considerations to automate the Bradford Hills causality assessment. We evaluated the framework on a drug safety gold standard know as the observational medical outcomes partnerships nonspecified association reference set. The methodology obtained excellent discriminate ability with area under the curves ranging between 0.792-0.940 (existing method optimal: 0.73) and a mean average precision of 0.640 (existing method optimal: 0.141). The proposed features can be calculated efficiently and be readily updated, making the framework suitable for big observational data.
Left ventricular assist devices (LVADs) are an increasingly common therapy for patients with advanced heart failure. However, implantation of the LVAD increases the risk of stroke, infection, bleeding, and other serious adverse events (AEs). Most post-LVAD AEs studies have focused on individual AEs in isolation, neglecting the possible interrelation, or causality between AEs. This study is the first to conduct an exploratory analysis to discover common sequential chains of AEs following LVAD implantation that are correlated with important clinical outcomes. This analysis was derived from 58,575 recorded AEs for 13,192 patients in International Registry for Mechanical Circulatory Support (INTERMACS) who received a continuousflow LVAD between 2006 and 2015. The pattern mining procedure involved three main steps: (1) creating a bank of AE sequences by converting the AEs for each patient into a single, chronologically sequenced record, (2) grouping patients with similar AE sequences using hierarchical clustering, and (3) extracting temporal chains of AEs for each group of patients using Markov modeling. The mined results indicate the existence of seven groups of sequential chains of AEs, characterized by common types of AEs that occurred in a unique order. The groups were identified as: GRP1: Recurrent bleeding, GRP2: Trajectory of device malfunction & explant, GRP3: Infection, GRP4: Trajectories to transplant, GRP5: Cardiac arrhythmia, GRP6: Trajectory of neurological dysfunction & death, and GRP7: Trajectory of respiratory failure, renal dysfunction & death. These patterns of sequential post-LVAD AEs disclose potential interdependence between AEs and may aid prediction, and prevention, of subsequent AEs in future studies.
In this paper, we extend graph-based identification methods by allowing background knowledge in the form of non-zero parameter values. Such information could be obtained, for example, from a previously conducted randomized experiment, from substantive understanding of the domain, or even an identification technique. To incorporate such information systematically, we propose the addition of auxiliary variables to the model, which are constructed so that certain paths will be conveniently cancelled. This cancellation allows the auxiliary variables to help conventional methods of identification (e.g., single-door criterion, instrumental variables, half-trek criterion), as well as model testing (e.g., d-separation, over-identification). Moreover, by iteratively alternating steps of identification and adding auxiliary variables, we can improve the power of existing identification methods via a bootstrapping approach that does not require external knowledge. We operationalize this method for simple instrumental sets (a generalization of instrumental variables) and show that the resulting method is able to identify at least as many models as the most general identification method for linear systems known to date. We further discuss the application of auxiliary variables to the tasks of model testing and z-identification.
Off-the-shelf biomedical embeddings obtained from the recently released various pre-trained language models (such as BERT, XLNET) have demonstrated state-of-the-art results (in terms of accuracy) for the various natural language understanding tasks (NLU) in the biomedical domain. Relation Classification (RC) falls into one of the most critical tasks. In this paper, we explore how to incorporate domain knowledge of the biomedical entities (such as drug, disease, genes), obtained from Knowledge Graph (KG) Embeddings, for predicting Drug-Drug Interaction from textual corpus. We propose a new method, BERTKG-DDI, to combine drug embeddings obtained from its interaction with other biomedical entities along with domain-specific BioBERT embedding-based RC architecture. Experiments conducted on the DDIExtraction 2013 corpus clearly indicate that this strategy improves other baselines architectures by 4.1% macro F1-score.
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