This guide will take approximately 5 minutes to complete.
In this guide you will learn:
- How to search for a known IMP-side effect relationship
- How to identify direct and indirect connections between the IMP and the side effect
Step 0: Log in
Refer to https://med.causaly.com
TIP! In case you’ve forgotten your password, you can recover it here.
Step 1: Explore the direct relationship between an IMP and an adverse event
Example: Azacitidine and Thrombocytopenic Purpura (Intelligent Search link)
To investigate whether an adverse event is associated with an IMP use the Intelligent Search on the Causaly home page (Figure 1).
Figure 1. The Intelligent Search on the Causaly homepage
Begin your search by typing the relevant keywords in the input box. The system will suggest relevant concepts below and you can select the most relevant ones to your search. In this example, start by typing “azacitidine” and then “thrombocytopenic purpura” (Figure 2).
Figure 2: Select the two concepts of interest to investigate the direct relationship between them in Intelligent Search.
Select the relationship between the two concepts from the list of proposed search topics to look for their direct associations. Causaly will look for the direct associations not only between the drug and the disorder of interest, but also for the narrower and related concepts included in this search.
TIP!
- Causaly will include narrower and related concepts by default, in order to increase the sensitivity of your search. You can review them by clicking on the “View related concepts” option of the IMP or disorder (Figure 3).
Figure 3: Explore the narrower and related concepts of the IMP or disorder.
- If you would like to increase the specificity of your search, click on the checkbox to deselect the concepts and exclude them from the search (Figure 4).
Figure 4: Deselect narrower and/or related concepts to increase the specificity of your search.
You can now browse the relationships in the Grid view (Figure 5).
Figure 5: The relationships between azacitidine and thrombocytopenic purpura and their respective narrower concepts (e.g. fanconi anemia, diamond-blackfan anemia 1, immune thrombocytopenic purpura, etc).
TIP! To find out more about a specific relationship, click on it and a sidebar will appear where you can review the evidence (Figure 6).
Figure 6: The sidebar with the supporting evidence appears when clicking on a relationship of interest.
Step 2: Refine results to publications that report a direct association between the two concepts
In the Articles view, you will find publications that report direct and indirect relationships between the IMP and the disorder. You can limit your results to the articles that describe a direct relationship between the two concepts by selecting “Direct relationship” under the “Document relevance” filter on the left of your screen (Intelligent Search link).
Looking for direct associations between a side effect and an IMP provides the answer to whether a known association exists or not. If the two concepts have already been linked in the existing biomedical literature, the above search strategy can be applied.
However, when there is no publication describing a relationship between an IMP and an adverse event, you can apply the following two approaches.
Option 1: Use a broader concept to describe the side effect of interest
You can increase results retrieval by broadening the scope of your search.
Example: Selumetinib and Thrombocytopenic Purpura
By exploring the relationship between “Selumetinib” and “Thrombocytopenic Purpura”, the articles retrieved do not show evidence of a direct relationship (Intelligent Search link). When the side effect is replaced with a broader concept such as “Thrombocytopenia”, the system will search for all abnormalities in platelet (thrombocyte) levels, including thrombocytopenic purpura (Intelligent Search link).
In this case, direct associations were found between Selumetinib and 2 other platelet-associated diseases (Figure 7).
Figure 7: The relationships between selumetinic and thrombocytopenia, and their respective narrower concepts (e.g. thrombocytopenia, pancytopenia etc).
TIP!
- Click on the “Save” button to save your search and create alerts. You will receive notifications when new data regarding a relationship of interest becomes available (Figure 8).
Figure 8. Click on the “Save” button to save searches.
- Learn more about how to select the best terms for your search here.
Option 2: Identify the indirect connections between the IMP and the side effect of interest
The rationale behind this approach is to understand the IMP’s mechanism of action (MoA) and link it to the pathophysiology of the adverse event. These are the cases in which the IMP does not directly induce the event but leads to an effect that may in turn trigger the observed side effect.
To do this, you can use Multi-hop analysis to look for the potential mediators or pathways through which an IMP may induce a side effect of interest. Access the Multi-hop analysis interface via the “Search” menu at the top of the page (Figure 9).
Figure 9: Access “Multi-Hop” at the top of the page to look for potential mediators or pathways.
To look for potential mediators between an IMP and a side effect of interest, enter the pharmaceutical product in Concept Box A and the disease or pathologic function in Concept Box C. In Concept Box B, select categories of interest under the Category tab to refine your results to the relevant potential mediators.
TIP! For more information on how to use Multi-hop analysis, please visit this step-by-step guide.
Example: Potential genes or proteins that mediate the effect of clofarabine on thrombocytopenic purpura (Multi-hop analysis link)
In this example, type “clofarabine” in Concept Box A and “thrombocytopenic purpura” in Concept Box C. In Concept Box B, select “Amino Acid, Peptide, or Protein” under the Chemicals & Drugs category and “Gene or Genome” under the Genes & Molecular Sequences category to find potential mediators between the two concepts.
Click search to view the results. You will find a list of genes and proteins that may mediate the effect of clofarabine on thrombocytopenic purpura (Figure 10).
Figure 10: Potential mediators by which clofarabine may affect thrombocytopenic purpura.
To examine the supporting evidence for the relationship between a mediator of interest and the IMP or the side effect of interest, click on the arrow (Figure 11). The sidebar appears where you can explore the articles and the associated evidence points.
Figure 11: Supporting evidence for the relationship between clofarabine and AKT1 gene.
TIP!
- To visualize all the different mediators, switch to the Network view at the top right corner of the results (Figure 12).
Figure 12: Visualization using the Network view.
- Based on what you consider as a mediator or pathway, you can select different categories in Concept Box B. For example, to search for biochemical pathways, you can select “Cell Function” and “Molecular Function” under the Physiology category (Figure 13).
Figure 13: Refine results to biochemical pathways using filters under the Physiology category.
- To further dive into the MoA, use Intelligent Search to explore the biochemical pathways that are affected by the IMP such as clofarabine (Intelligent Search link), and/or those that affect the pathophysiology of the adverse event such as thrombocytopenic purpura (Intelligent Search link). In both cases, the results will appear in an interactive dendrogram view so that you can explore all the pathways at a glance (Figure 14).
Figure 14: Cell functions affecting the pathophysiology of thrombocytopenic purpura.