MedDRA and Ontology

Dr. Mélanie Courtot, mcourtot@gmail.com

Brinkman lab, Simon Fraser University

Hsiao lab, BC Public Health Microbiology and Research Laboratory

Part I The Logic of Surveillance Guidelines: An Analysis of Vaccine Adverse Event Reports from an Ontological Perspective

Background and problem statement

• Surveillance of Adverse Events Following Immunization is important• Detection of issues with vaccine • Importance of vaccine-risk communication

• Analysis of AE reports is a subjective, time- and money costly process• Manual review of the textual reports

The Brighton collaboration

• https://brightoncollaboration.org• Provides case definitions and guidelines to standardize

reporting• Well established network (adopted as standard in Canada

2009)

Hypothesis

Encoding Brighton guidelines in OWL allows automated classification of adverse events at similar accuracy

Test case

• VAERS dataset• Vaccine Adverse Event Reporting System• 6032 reports: ~5800 negative, ~230 positive• Post H1N1 immunization 2009/2010• Manually classified for anaphylaxis

• MedDRA (Medical Dictionary of Regulatory Activities) is used to represent clinical findings

Example VAERS report

Automated Diagnosis workflow

Results

At best cut-off point: Sensitivity 57%Specificity 97%

Standardized MedDRA Queries

• SMQs are an existing MedDRA-based screening method

• Retrieval of documents based on Anaphylaxis SMQ alone only fair: 54% sensitivity, 97% specificity

• Idea: • Identify MedDRA terms that are significantly associated

with the diagnosis outcome using contingency tables• Augment the existing MedDRA SMQ with those terms

Cosine similarity method• Represent documents (query and report) as vectors of

terms• Compare the cosine measure of the angle they form

Cosine ~ 1Query ~ Report

Cosine ~ 0Query != Report

Example• Vector MEDDRA SMQ:

’Choking', 'Cough’, ’Oedema’, 'Rash’

• Vector REPORT#72:

’Oedema’, 'Rash’, ‘Vomiting’

• Vector REPORT#104:

‘Palpitations’, ‘Fatigue’, Neuropathy’

Results - Expanded MedDRA SMQ

At best cut-off point: Sensitivity 92%, Specificity 87%

Automate classification of adverse events

• Using a MedDRA- based mapping, I successfully encoded existing clinical guidelines for adverse events classification

• I also suggested ways to detect terms of importance when analyzing MedDRA annotated reports

• This allows for faster

and cheaper detection

of potential safety issues.

Publication

Acknowledgements

• Ryan Brinkman, BC Cancer Agency, Vancouver, Canada

• Alan Ruttenberg, University at Buffalo, New York, USA

• Julie Lafleche, Robert Pless, Barbara Law, Public Health Agency of Canada, Ottawa, Ontario

• Jan Bonhoeffer, Brighton Collaboration, Basel, Switzerland

• Patrick Revelle, MSSO

Part IISupport MedDRA with ontology

Current encoding of reports

MedDRA coding (1) done in second step, post report collection at the national level (2) by specifically trained coders (3) not in contact with the patient or physician who saw the patient

Definitions

• PHAC, User Guide to completion and submission of the AEFI reports, http://www.phac-aspc.gc.ca/im/pdf/AEFI-ug-gu-eng.pdf

• Abdominal pain:  Sensation of discomfort or pain in the abdominal region. (BCCD: Vaccine 28 (2010) 4487-4498)

• Potential to use SNOMED mappings to start adding definitions

Decomposition of terms• Application site

• Perforated, atrophy, dermatitis, erythema, ulcer• HLT = Application and instillation site reactions• HLGT = Administration site reactions• SOC = General disorders and administration site conditions

• Gastric ulcer• “stomach” and “ulcer”• Ulcer = http://purl.bioontology.org/ontology/MEDDRA/10045285

Location• Abdominal pain = pain which occurs in the abdomen

Foundational Model of Anatomy

Foundational Model Explorer, http://fme.biostr.washington.edu/FME/index.html

Ability to classify according to different guidelines

• For example, the Brighton collaboration guidelines for adverse events following immunization

• Recognized need from the community: an SMQ for seizure according to the Brighton case definition has been added to MedDRA, others were in progress (early 2014)

Guideline classification• A MedDRA term “abdominal pain”, defined as “pain and

occurs in abdomen” can be reconciled with another term such as “abdominal symptoms” -> even though the latter wouldn’t be defined in MedDRA, a reasoner would automatically infer the correct hierarchy

Report #12345

Abdominal painRashFever

+

Clinical Guideline

AbdominalsymptomAndDermatologicalsymptom

Reasoner Diagnosis X according to clinical guideline

ReasonerDiagnosis X2 according to clinical guideline 2

Example: Brighton anaphylaxisLevel 1

Hierarchy depth• Constraint on the hierarchy depth: MedDRA has only 5

levels• System organ class (SOC)• High Level Group Term (HGLT)• High Level Term (HLT)• Preferred Term (PT)• Lowest Level Term (LLT)

• Relationship between LLTs and PTs not always well defined• LLTs (e.g., “Junctional bradycardia”, “Junctional tachycardia” and

“Reciprocating tachycardia”) that are not synonymous with each other or to their associated PT (e.g., “Nodal arrhythmia”).

Richesson 2008, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2575842/

Formalization of relations between terms

• Relations between LLTs (and PTs) could be formally defined

(1) Terms can have synonyms (“alternative terms” in the OBO Foundry)

(2) Terms can be related using SKOS relations such as “broader synonyms” or “narrower synonyms”, though ultimately we would like to have different classes created

(3) OWL supports multiple languages for terms via lang attribute

Subsumption

• VAERS 370841;positive for anaphylaxis

• "As reported by mother, at 11 AM child screamed with abdominal and stomach pain. Mother called Drs. office and talked with nurse who said the symptoms should go away and if they didn't bring child in. Pain subsided in 30 minutes. No more complaints until 11/25/09 and child reported stomach pain again and at this time had difficulty swallowing solid food. Could drink liquids without difficulty. On 11/26/09 through 11/28/09 child demonstrated no symptoms other than when asked the child would state his stomach hurt. On 11/29/09 child would not eat. Mom called Drs. office and talked to the nurse, relating symptoms and telling nurse childs lips were purplish. Nurse said to take child to the ER. Blood and urine tests, as well as X-Rays done at ER. Mother states Dr. said he couldn't find anything wrong and child should not be having these symptoms. Sent home from ER. On 11/30/09 mother called Drs. office and nurse said to bring child in. Dr. ran some more tests which came out normal. Mother states Dr. called the drug (H1N1) company and was told they had not had any such symptoms reported. Dr. talked with another Dr. in office and decided it was an allergic reaction to the H1N1 vaccination received on 11/20/09. Prednisolone 15 mg. per ml. take 7.5 ml. per day po prescribed for child. On 12/01/09 mother states child still cannot eat but not screaming with stomach pain. 12/10/11/21/2009 ED records for 11/29/2009, c/o's abdominal pain, lack of appetite, dysphagia, cyanotic around mouth and lips 12/10/2009”

• Abdominal pain;10000081;Abdominal pain upper;10000087;Barium swallow normal;10004126;Blood glucose increased;10005557;Blood potassium decreased;10005724;

SMQsStandardized MedDRA Queries

Ability to add new SMQs• Based on different guidelines (e.g., Brighton)• Could be developed by users using the MedDRA terms

directly• Would be easier to maintain using the subsumption

hierarchy • if one term is added under one existing terms, it would get

automatically included• Annotating with “abdominal pain upper” would automatically imply

“abdominal pain”

Other applications• Add temporal descriptors, and provide time related

relation• “sudden onset”• “rapid progression”• “is preceded by”

• Check consistency at data entry time?

In summary

1. Add definitions to PTs

2. Add relations such as location of the adverse event

3. Have a reasoner classify the resulting ontology

4. In each anatomical system group, check and add relations between PTs (e.g. abdominal pain lower is_a abdominal pain)

5. Repeat for LLTs